Redox regulation of cancer stem cells: Biology and therapeutic implications

Abstract

Cancer stem cells (CSCs) are a small group of tumor cells with the capacity to undergo self-renewal and differentiation. These cells not only initiate and maintain tumor growth, but also confer resistance to current cancer therapies. CSCs display a high degree of plasticity and can be generated under therapeutic stress via dedifferentiation from non-stem-like tumor cells, suggesting the necessity simultaneously targeting CSCs and bulk tumor cells to achieve the best therapeutic effect. Despite the findings that therapeutic stress induces CSC plasticity, the mechanisms underpinning CSC formation and therapeutic resistance are not fully defined. Tumor cells display elevated levels of reactive oxygen species (ROS), contributed by rapid proliferation, enhanced metabolic demands and oncogenic signaling. CSCs achieve redox homeostasis partly by regulating redox-sensitive transcription factors (TFs), including NRF2, HIF-1α, BACH1, NF-kB, FOXOs, AP-1, and others. This review aims to summarize the roles and underlying mechanisms of these TFs in regulation of CSCs and tumor progression from the perspectives of stem cell maintenance, metabolic reprogramming, epithelial-mesenchymal transition (EMT) and angiogenesis. We also discuss the potentials of utilizing specific inhibitors for these TFs in suppressing drug resistance and metastasis by repressing CSC activity, an approach that may provide new targeted therapies for advanced cancer and improve patient outcome.

Keywords

cancer stem cells (CSCs) / epithelial–mesenchymal plasticity / reactive oxygen species (ROS) / redox-sensitive transcription factors / therapeutic resistance

References

[1] PragerBC, XieQ, BaoS, RichJN. Cancer stem cells: the architects of the tumor ecosystem. Cell Stem Cell. 2019;24(1):41-53.

[2] MageeJA, Piskounova E, MorrisonSJ. Cancer stem cells: impact, heterogeneity, and uncertainty. Cancer Cell. 2012;21(3):283-296.

[3] MeachamCE, Morrison SJ. Tumour heterogeneity and cancer cell plasticity. Nature. 2013;501(7467):328-337.

[4] WichaMS, LiuS, DontuG. Cancer stem cells: an old idea--a paradigm shift. Cancer Res. 2006;66(4):1883-1890;discussion 1895.

[5] KakaralaM, WichaMS. Implications of the cancer stem-cell hypothesis for breast cancer prevention and therapy. J Clin Oncol. 2008;26(17):2813-2820.

[6] BomanBM, WichaMS. Cancer stem cells: a step toward the cure. J Clin Oncol. 2008;26(17):2795-2799.

[7] BonnetD, DickJE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nature Med. 1997;3(7):730-737.

[8] Al-HajjM, WichaMS, Benito-HernandezA, MorrisonSJ, ClarkeMF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci. 2003;100(7):3983-3988.

[9] GinestierC, HurMH, Charafe-JauffretE, et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell. 2007;1(5):555-567.

[10] LiC, HeidtDG, DalerbaP, et al. Identification of pancreatic cancer stem cells. Cancer Res. 2007;67(3):1030-1037.

[11] PatrawalaL, Calhoun T, Schneider-BroussardR, et al. Highly purified CD44+prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells. Oncogene. 2006;25(12):1696-1708.

[12] CollinsAT, BerryPA, HydeC, Stower MJ, MaitlandNJ. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res. 2005;65(23):10946-10951.

[13] O’BrienCA, Pollett A, GallingerS, DickJE. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature. 2007;445(7123):106-110.

[14] Ricci-VitianiL, Lombardi DG, PilozziE, et al. Identification and expansion of human colon-cancer-initiating cells. Nature. 2007;445(7123):111-115.

[15] MaS, ChanK-W, HuL, et al. Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology. 2007;132(7):2542-2556.

[16] MaS, TangKH, ChanYP, et al. miR-130b promotes CD133(+) liver tumor-initiating cell growth and self-renewal via tumor protein 53-induced nuclear protein 1. Cell Stem Cell. 2010;7(6):694-707.

[17] KimCFB, Jackson EL, WoolfendenAE, et al. Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell. 2005;121(6):823-835.

[18] PrinceME, Sivanandan R, KaczorowskiA, et al. Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci. 2007;104(3):973-978.

[19] SinghSK, Hawkins C, ClarkeID, et al. Identification of human brain tumour initiating cells. Nature. 2004;432(7015):396-401.

[20] LuoM, Clouthier SG, DeolY, et al. Breast cancer stem cells: current advances and clinical implications. Methods Mol Biol. 2015;1293:1.

[21] VisvaderJE, StinglJ. Mammary stem cells and the differentiation hierarchy: current status and perspectives. Genes Dev. 2014;28(11):1143-1158.

[22] VisvaderJE. Cells of origin in cancer. Nature. 2011;469(7330):314-322.

[23] ChafferCL, Brueckmann I, ScheelC, et al. Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state. Proc Natl Acad Sci. 2011;108(19):7950-7955.

[24] Friedmann-MorvinskiD, Verma IM. Dedifferentiation and reprogramming: origins of cancer stem cells. EMBO Rep. 2014;15(3):244-253.

[25] LuH, Samanta D, XiangL, et al. Chemotherapy triggers HIF-1-dependent glutathione synthesis and copper chelation that induces the breast cancer stem cell phenotype. Proc Natl Acad Sci. 2015;112(33):E4600.

[26] LuH, XieY, TranL, et al. Chemotherapy-induced S100A10 recruits KDM6A to facilitate OCT4-mediated breast cancer stemness. J Clin Invest. 2020;130(9):4607-4623.

[27] SchieberM, Chandel NS. ROS function in redox signaling and oxidative stress. Curr Biol. 2014;24(10):R453-R462.

[28] ForcadosGE, JamesDB, SallauAB, Muhammad A, MabetaP. Oxidative stress and carcinogenesis: potential of phytochemicals in breast cancer therapy. Nutr Cancer. 2017;69(3):365-374.

[29] MoloneyJN, CotterTG. ROS signalling in the biology of cancer. Semin Cell Dev Biol. 2018;80:50-64.

[30] TuyK, Rickenbacker L, HjelmelandAB. Reactive oxygen species produced by altered tumor metabolism impacts cancer stem cell maintenance. Redox Biol. 2021;44:101953.

[31] SemenzaGL. Hypoxia-inducible factors: coupling glucose metabolism and redox regulation with induction of the breast cancer stem cell phenotype. EMBO J. 2017;36(3):252-259.

[32] WielC, Le GalK, IbrahimMX, et al. BACH1 stabilization by antioxidants stimulates lung cancer metastasis. Cell. 2019;178(2):330-345.e22.

[33] LuoM, ShangL, BrooksMD, et al. Targeting breast cancer stem cell state equilibrium through modulation of redox signaling. Cell Metab. 2018;28(1):69-86.e6.

[34] MyantKB, Cammareri P, McGheeEJ, et al. ROS production and NF-κB activation triggered by RAC1 facilitate WNT-driven intestinal stem cell proliferation and colorectal cancer initiation. Cell Stem Cell. 2013;12(6):761-773.

[35] Coomans de BrachèneA, DemoulinJ-B. FOXO transcription factors in cancer development and therapy. Cell Mol Life Sci. 2016;73(6):1159-1172.

[36] JiramongkolY, LamEW-F. FOXO transcription factor family in cancer and metastasis. Cancer Metastasis Rev. 2020;39(3):681-709.

[37] LiuS, CongY, WangD, et al. Breast cancer stem cells transition between epithelial and mesenchymal states reflective of their normal counterparts. Stem Cell Rep. 2014;2(1):78-91.

[38] JollyMK, Somarelli JA, ShethM, et al. Hybrid epithelial/mesenchymal phenotypes promote metastasis and therapy resistance across carcinomas. Pharmacol Ther. 2019;194:161-184.

[39] PastushenkoI, Brisebarre A, SifrimA, et al. Identification of the tumour transition states occurring during EMT. Nature. 2018;556(7702):463-468.

[40] LuoM, BrooksM, WichaM. Epithelial-mesenchymal plasticity of breast cancer stem cells: implications for metastasis and therapeutic resistance. Curr Pharm Des. 2015;21(10):1301-1310.

[41] BrooksMD, Burness ML, WichaMS. Therapeutic implications of cellular heterogeneity and plasticity in breast cancer. Cell Stem Cell. 2015;17(3):260-271.

[42] JuanCA, Pérez de la Lastra JM, PlouFJ, Pérez-LebeñaE. The chemistry of reactive oxygen species (ROS) revisited: outlining their role in biological macromolecules (DNA, lipids and proteins) and induced pathologies. Int J Mol Sci. 2021;22(9):4642.

[43] HayesJD, Dinkova-Kostova AT, TewKD. Oxidative stress in cancer. Cancer Cell. 2020;38(2):167-197.

[44] FujiiJ, HommaT, OsakiT. Superoxide radicals in the execution of cell death. Antioxidants. 2022;11(3):501.

[45] MaillouxRJ. An update on mitochondrial reactive oxygen species production. Antioxidants. 2020;9(6):472.

[46] ŚciskalskaM, Ołdakowska M, MarekG, MilnerowiczH. Changes in the activity and concentration of superoxide dismutase isoenzymes (Cu/Zn SOD, MnSOD) in the blood of healthy subjects and patients with acute pancreatitis. Antioxidants. 2020;9(10):948.

[47] KimJJ, LeeSB, ParkJK, Yoo YD. TNF-α-induced ROS production triggering apoptosis is directly linked to Romo1 and Bcl-XL. Cell Death Differ. 2010;17(9):1420-1434.

[48] CiavardelliD, RossiC, BarcaroliD, et al. Breast cancer stem cells rely on fermentative glycolysis and are sensitive to 2-deoxyglucose treatment. Cell Death Dis. 2014;5(7):e1336.

[49] FengW, Gentles A, NairRV, et al. Targeting unique metabolic properties of breast tumor initiating cells. Stem Cells. 2014;32(7):1734-1745.

[50] LambR, Bonuccelli G, OzsváriB, et al. Mitochondrial mass, a new metabolic biomarker for stem-like cancer cells: understanding WNT/FGF-driven anabolic signaling. Oncotarget. 2015;6(31):30453-30471.

[51] JaganjacM, Milkovic L, SunjicSB, ZarkovicN. The NRF2, thioredoxin, and glutathione system in tumorigenesis and anticancer therapies. Antioxidants. 2020;9(11):1151.

[52] BryanHK, Olayanju A, GoldringCE, ParkBK. The Nrf2 cell defence pathway: Keap1-dependent and -independent mechanisms of regulation. Biochem Pharmacol. 2013;85(6):705-717.

[53] CanningP, Sorrell FJ, BullockAN. Structural basis of Keap1 interactions with Nrf2. Free Radic Biol Med. 2015;88(Pt B):101-107.

[54] HirotsuY, Katsuoka F, FunayamaR, et al. Nrf2-MafG heterodimers contribute globally to antioxidant and metabolic networks. Nucleic Acids Res. 2012;40(20):10228-10239.

[55] UlasovAV, Rosenkranz AA, GeorgievGP, SobolevAS. Nrf2/Keap1/ARE signaling: towards specific regulation. Life Sci. 2022;291:120111.

[56] Silva-IslasCA, Maldonado PD. Canonical and non-canonical mechanisms of Nrf2 activation. Pharmacol Res. 2018;134:92-99.

[57] KomatsuM, Kurokawa H, WaguriS, et al. The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nature Cell Biol. 2010;12(3):213-223.

[58] CampND, JamesRG, DawsonDW, et al. Wilms tumor gene on X chromosome (WTX) inhibits degradation of NRF2 protein through competitive binding to KEAP1 protein. J Biol Chem. 2012;287(9):6539-6550.

[59] HastBE, Goldfarb D, MulvaneyKM, et al. Proteomic analysis of ubiquitin ligase KEAP1 reveals associated proteins that inhibit NRF2 ubiquitination. Cancer Res. 2013;73(7):2199-2210.

[60] KangJ-S, NamLB, YooO-K, Keum Y-S. Molecular mechanisms and systemic targeting of NRF2 dysregulation in cancer. Biochem Pharmacol. 2020;177:114002.

[61] GorriniC, Baniasadi PS, HarrisIS, et al. BRCA1 interacts with Nrf2 to regulate antioxidant signaling and cell survival. J Exp Med. 2013;210(8):1529-1544.

[62] PanieriE, PinhoSA, AfonsoGJM, Oliveira PJ, Cunha-OliveiraT, SasoL. NRF2 and mitochondrial function in cancer and cancer stem cells. Cells. 2022;11(15):2401.

[63] ChowdhryS, ZhangY, McMahonM, Sutherland C, CuadradoA, HayesJD. Nrf2 is controlled by two distinct β-TrCP recognition motifs in its Neh6 domain, one of which can be modulated by GSK-3 activity. Oncogene. 2013;32(32):3765-3781.

[64] ChangC-W, ChenY-S, TsayY-G, et al. ROS-independent ER stress-mediated NRF2 activation promotes warburg effect to maintain stemness-associated properties of cancer-initiating cells. Cell Death Dis. 2018;9(2):194.

[65] DeyP, Kimmelman AC, DePinhoRA. Metabolic codependencies in the tumor microenvironment. Cancer Discovery. 2021;11(5):1067-1081.

[66] DeBerardinisRJ, Chandel NS. Fundamentals of cancer metabolism. Sci Adv. 2016;2(5):e1600200.

[67] ZhuJ, Thompson CB. Metabolic regulation of cell growth and proliferation. Nat Rev Mol Cell Biol. 2019;20(7):436-450.

[68] MitsuishiY, Taguchi K, KawataniY, et al. Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell. 2012;22(1):66-79.

[69] MullarkyE, Cantley LC. Diverting glycolysis to combat oxidative stress. In: Nakao K, Minato N, Uemoto S, eds, Innovative Medicine: Basic Research and Development. Springer;2015:3-23.

[70] WuKC, CuiJY, KlaassenCD. Beneficial role of Nrf2 in regulating NADPH generation and consumption. Toxicol Sci. 2011;123(2):590-600.

[71] DengR, ZhengZ, HuS, et al. Loss of Nrf1 rather than Nrf2 leads to inflammatory accumulation of lipids and reactive oxygen species in human hepatoma cells, which is alleviated by 2-bromopalmitate. Biochim Biophys Acta Molec Cell Res. 2024;1871(2):119644.

[72] SunQ, XingX, WangH, et al. SCD1 is the critical signaling hub to mediate metabolic diseases: mechanism and the development of its inhibitors. Biomed Pharmacother. 2024;170:115586.

[73] FlowersMT, NtambiJM. Role of stearoyl-coenzyme A desaturase in regulating lipid metabolism. Curr Opin Lipidol. 2008;19(3):248-256.

[74] LudtmannMHR, Angelova PR, ZhangY, AbramovAY, Dinkova-Kostova AT. Nrf2 affects the efficiency of mitochondrial fatty acid oxidation. Biochem J. 2014;457(3):415-424.

[75] SamecM, Mazurakova A, LucanskyV, et al. Flavonoids attenuate cancer metabolism by modulating lipid metabolism, amino acids, ketone bodies and redox state mediated by Nrf2. Eur J Pharmacol. 2023;949:175655.

[76] BottAJ, ShenJ, TonelliC, et al. Glutamine anabolism plays a critical role in pancreatic cancer by coupling carbon and nitrogen metabolism. Cell Rep. 2019;29(5):1287-1298.e6.

[77] YooHC, YuYC, SungY, Han JM. Glutamine reliance in cell metabolism. Exp Mol Med. 2020;52(9):1496-1516.

[78] MokhtarzadehA, Hassanpour S, VahidZF, et al. Nano-delivery system targeting to cancer stem cell cluster of differentiation biomarkers. J Control Release. 2017;266:166-186.

[79] RyooI, ChoiB, KuS-K, Kwak M-K. High CD44 expression mediates p62-associated NFE2L2/NRF2 activation in breast cancer stem cell-like cells: implications for cancer stem cell resistance. Redox Biol. 2018;17:246-258.

[80] ChoiB-H, RyooI, SimKH, Ahn H, LeeYJ, KwakM-K. High levels of hyaluronic acid synthase-2 mediate NRF2-driven chemoresistance in breast cancer cells. Biomol Ther. 2022;30(4):368-379.

[81] ParkJ, KimSK, HallisSP, Choi B-H, KwakM-K. Role of CD133/NRF2 axis in the development of colon cancer stem cell-like properties. Front Oncol. 2021;11:808300.

[82] KimD, ChoiB, RyooI, Kwak M-K. High NRF2 level mediates cancer stem cell-like properties of aldehyde dehydrogenase (ALDH)-high ovarian cancer cells: inhibitory role of all-trans retinoic acid in ALDH/NRF2 signaling. Cell Death Dis. 2018;9(9):896.

[83] MizunoT, SuzukiN, MakinoH, et al. Cancer stem-like cells of ovarian clear cell carcinoma are enriched in the ALDH-high population associated with an accelerated scavenging system in reactive oxygen species. Gynecol Oncol. 2015;137(2):299-305.

[84] LamouilleS, XuJ, DerynckR. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15(3):178-196.

[85] LambertAW, Weinberg RA. Linking EMT programmes to normal and neoplastic epithelial stem cells. Nat Rev Cancer. 2021;21(5):325-338.

[86] Vilchez MercedesSA, Bocci F, AhmedM, et al. Nrf2 modulates the hybrid epithelial/mesenchymal phenotype and notch signaling during collective cancer migration. Front Mol Biosci. 2022;9:807324.

[87] FengR, MorineY, IkemotoT, et al. Nrf2 activation drive macrophages polarization and cancer cell epithelial-mesenchymal transition during interaction. Cell Commun Signaling. 2018;16(1):54.

[88] Čipak GašparovićA, MilkovićL, Dandachi N, et al. Chronic oxidative stress promotes molecular changes associated with epithelial mesenchymal transition, NRF2, and breast cancer stem cell phenotype. Antioxidants. 2019;8(12):633.

[89] HongX, MaN, LiD, et al. UBE2E2 enhances snail-mediated epithelial-mesenchymal transition and Nrf2-mediated antioxidant activity in ovarian cancer. Cell Death Dis. 2023;14(2):100.

[90] LiD, HongX, ZhaoF, Ci X, ZhangS. Targeting Nrf2 may reverse the drug resistance in ovarian cancer. Cancer Cell Int. 2021;21(1):116.

[91] ShangQ, PanC, ZhangX, et al. Nuclear factor Nrf2 promotes glycosidase OGG1 expression by activating the AKT pathway to enhance leukemia cell resistance to cytarabine. J Biol Chem. 2023;299(1):102798.

[92] MirzaeiS, Zarrabi A, HashemiF, et al. Nrf2 signaling pathway in chemoprotection and doxorubicin resistance: potential application in drug discovery. Antioxidants. 2021;10(3):349.

[93] MukhopadhyayS, Goswami D, AdiseshaiahPP, et al. Undermining glutaminolysis bolsters chemotherapy while NRF2 promotes chemoresistance in KRAS-driven pancreatic cancers. Cancer Res. 2020;80(8):1630-1643.

[94] CucciMA, Grattarola M, MongeC, et al. Nrf2 as a therapeutic target in the resistance to targeted therapies in melanoma. Antioxidants. 2023;12(6):1313.

[95] ZhouY, ChenY, ShiY, et al. FAM117B promotes gastric cancer growth and drug resistance by targeting the KEAP1/NRF2 signaling pathway. J Clin Invest. 2023;133(3):e158705.

[96] SargaziZ, Yazdani Y, TahavvoriA, et al. NFR2/ABC transporter axis in drug resistance of breast cancer cells. Mol Biol Rep. 2023;50(6):5407-5414.

[97] EelenG, TrepsL, LiX, Carmeliet P. Basic and therapeutic aspects of angiogenesis updated. Circ Res. 2020;127(2):310-329.

[98] ZhouS, YeW, ZhangM, Liang J. The effects of Nrf2 on tumor angiogenesis: a review of the possible mechanisms of action. Crit Rev Eukaryot Gene Expr. 2012;22(2):149-160.

[99] JiX, WangH, ZhuJ, et al. Knockdown of Nrf2 suppresses glioblastoma angiogenesis by inhibiting hypoxia-induced activation of HIF-1α. Int J Cancer. 2014;135(3):574-584.

[100] ChenZ, HanF, DuY, ShiH, ZhouW. Hypoxic microenvironment in cancer: molecular mechanisms and therapeutic interventions. Signal Transduct Target Ther. 2023;8(1):70.

[101] WicksEE, Semenza GL. Hypoxia-inducible factors: cancer progression and clinical translation. J Clin Invest. 2022;132(11):e159839.

[102] SchitoL, Semenza GL. Hypoxia-inducible factors: master regulators of cancer progression. Trends Cancer. 2016;2(12):758-770.

[103] CorradoC, Fontana S. Hypoxia and HIF signaling: one axis with divergent effects. Int J Mol Sci. 2020;21(16):5611.

[104] AlbadariN, DengS, LiW. The transcriptional factors HIF-1 and HIF-2 and their novel inhibitors in cancer therapy. Expert Opin Drug Discovery. 2019;14(7):667-682.

[105] RuasJL, Berchner-Pfannschmidt U, MalikS, et al. Complex regulation of the transactivation function of hypoxia-inducible factor-1αby direct interaction with two distinct domains of the CREB-binding protein/p300. J Biol Chem. 2010;285(4):2601-2609.

[106] SoniS, PadwadYS. HIF-1 in cancer therapy: two decade long story of a transcription factor. Acta Oncol. 2017;56(4):503-515.

[107] KieransSJ, TaylorCT. Regulation of glycolysis by the hypoxia-inducible factor (HIF): implications for cellular physiology. J Physiol. 2021;599(1):23-37.

[108] BaoMH-R, WongCC-L. Hypoxia, metabolic reprogramming, and drug resistance in liver cancer. Cells. 2021;10(7):1715.

[109] LuoW, HuH, ChangR, et al. Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell. 2011;145(5):732-744.

[110] SinghL, NairL, KumarD, et al. Hypoxia induced lactate acidosis modulates tumor microenvironment and lipid reprogramming to sustain the cancer cell survival. Front Oncol. 2023;13:1034205.

[111] KaragiotaA, Kanoura A, ParaskevaE, SimosG, Chachami G. Pyruvate dehydrogenase phosphatase 1 (PDP1) stimulates HIF activity by supporting histone acetylation under hypoxia. FEBS J. 2023;290(8):2165-2179.

[112] TaylorCT, ScholzCC. The effect of HIF on metabolism and immunity. Nat Rev Nephrol. 2022;18(9):573.

[113] LiY, SunX-X, QianDZ, Dai M-S. Molecular crosstalk between MYC and HIF in cancer. Front Cell Dev Biol. 2020;8:590576.

[114] LuQ, YanS, SunH, et al. Akt inhibition attenuates rasfonin-induced autophagy and apoptosis through the glycolytic pathway in renal cancer cells. Cell Death Dis. 2015;6(12):e2005.

[115] DupuyF, Tabariès S, AndrzejewskiS, et al. PDK1-dependent metabolic reprogramming dictates metastatic potential in breast cancer. Cell Metab. 2015;22(4):577-589.

[116] DuW, ZhangL, Brett-MorrisA, et al. HIF drives lipid deposition and cancer in ccRCC via repression of fatty acid metabolism. Nat Commun. 2017;8(1):1769.

[117] TriantafyllouE-A, Georgatsou E, MylonisI, SimosG, Paraskeva E. Expression of AGPAT2, an enzyme involved in the glycerophospholipid/triacylglycerol biosynthesis pathway, is directly regulated by HIF-1 and promotes survival and etoposide resistance of cancer cells under hypoxia. Biochim Biophys Acta Molec Cell Bio Lipids. 2018;1863(9):1142-1152.

[118] ChappellJC, PayneLB, RathmellWK. Hypoxia, angiogenesis, and metabolism in the hereditary kidney cancers. J Clin Invest. 2019;129(2):442-451.

[119] GameiroPA, YangJ, MeteloAM, et al. In vivo HIF-mediated reductive carboxylation is regulated by citrate levels and sensitizes VHL-deficient cells to glutamine deprivation. Cell Metab. 2013;17(3):372-385.

[120] MaZ, WangLZ, ChengJ-T, et al. Targeting hypoxia-inducible factor-1-mediated metastasis for cancer therapy. Antioxid Redox Signal. 2021;34(18):1484-1497.

[121] ConleySJ, Gheordunescu E, KakaralaP, et al. Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia. Proc Natl Acad Sci. 2012;109(8):2784-2789.

[122] Pàez-RibesM, Allen E, HudockJ, et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell. 2009;15(3):220-231.

[123] MarholdM, Tomasich E, El-GazzarA, et al. HIF1αregulates mTOR signaling and viability of prostate cancer stem cells. Mol Cancer Res. 2015;13(3):556-564.

[124] LiuX, XieP, HaoN, et al. HIF-1-regulated expression of calreticulin promotes breast tumorigenesis and progression through Wnt/β-catenin pathway activation. Proc Natl Acad Sci. 2021;118(44):e2109144118.

[125] ByunJ-Y, HuangK, LeeJS, et al. Targeting HIF-1α/NOTCH1 pathway eliminates CD44+cancer stem-like cell phenotypes, malignancy, and resistance to therapy in head and neck squamous cell carcinoma. Oncogene. 2022;41(9):1352-1363.

[126] WangY, LiuY, MalekSN, Zheng P, LiuY. Targeting HIF1αeliminates cancer stem cells in hematological malignancies. Cell Stem Cell. 2011;8(4):399-411.

[127] LamK-H, MaS. Noncellular components in the liver cancer stem cell niche: biology and potential clinical implications. Hepatology. 2023;78(3):991-1005.

[128] XiongG, Stewart RL, ChenJ, et al. Collagen prolyl 4-hydroxylase 1 is essential for HIF-1αstabilization and TNBC chemoresistance. Nat Commun. 2018;9(1):4456.

[129] LinY-T, WuK-J. Epigenetic regulation of epithelial-mesenchymal transition: focusing on hypoxia and TGF-βsignaling. J Biomed Sci. 2020;27(1):39.

[130] SamantaD, ParkY, NiX, et al. Chemotherapy induces enrichment of CD47+/CD73+/PDL1+immune evasive triple-negative breast cancer cells. Proc Natl Acad Sci. 2018;115(6):E1239.

[131] ZhangH, LuH, XiangL, et al. HIF-1 regulates CD47 expression in breast cancer cells to promote evasion of phagocytosis and maintenance of cancer stem cells. Proc Natl Acad Sci. 2015;112(45):E6215.

[132] LiaoC-P, LinT-P, LiP-C, et al. Loss of MAOA in epithelia inhibits adenocarcinoma development, cell proliferation and cancer stem cells in prostate. Oncogene. 2018;37(38):5175-5190.

[133] PayneSJ, JonesL. Influence of the tumor microenvironment on angiogenesis. Future Oncol. 2011;7(3):395-408.

[134] HapkeRY, HaakeSM. Hypoxia-induced epithelial to mesenchymal transition in cancer. Cancer Lett. 2020;487:10-20.

[135] LeiJ, MaJ, MaQ, et al. Hedgehog signaling regulates hypoxia induced epithelial to mesenchymal transition and invasion in pancreatic cancer cells via a ligand-independent manner. Mol Cancer. 2013;12:66.

[136] ZhangQ, BaiX, ChenW, et al. Wnt/β-catenin signaling enhances hypoxia-induced epithelial-mesenchymal transition in hepatocellular carcinoma via crosstalk with hif-1αsignaling. Carcinogenesis. 2013;34(5):962-973.

[137] LeeJ-Y, KongG. Roles and epigenetic regulation of epithelial-mesenchymal transition and its transcription factors in cancer initiation and progression. Cell Mol Life Sci. 2016;73(24):4643-4660.

[138] YangM-H, WuM-Z, ChiouS-H, et al. Direct regulation of TWIST by HIF-1αpromotes metastasis. Nature Cell Biol. 2008;10(3):295-305.

[139] LiC-W, XiaW, HuoL, et al. Epithelial-mesenchymal transition induced by TNF-αrequires NF-κB-mediated transcriptional upregulation of Twist1. Cancer Res. 2012;72(5):1290-1300.

[140] NomuraA, Majumder K, GiriB, et al. Inhibition of NF-kappa B pathway leads to deregulation of epithelial-mesenchymal transition and neural invasion in pancreatic cancer. Lab Invest. 2016;96(12):1268-1278.

[141] RohwerN, CramerT. Hypoxia-mediated drug resistance: novel insights on the functional interaction of HIFs and cell death pathways. Drug Resist Updates. 2011;14(3):191-201.

[142] LiH-S, ZhouY-N, LiL, et al. HIF-1αprotects against oxidative stress by directly targeting mitochondria. Redox Biol. 2019;25:101109.

[143] SchöningJP, Monteiro M, GuW. Drug resistance and cancer stem cells: the shared but distinct roles of hypoxia-inducible factors HIF1αand HIF2α. Clin Exp Pharmacol Physiol. 2017;44(2):153-161.

[144] WalmsleySR, PrintC, FarahiN, et al. Hypoxia-induced neutrophil survival is mediated by HIF-1α-dependent NF-κB activity. J Exp Med. 2005;201(1):105-115.

[145] JiangX, WangJ, DengX, et al. The role of microenvironment in tumor angiogenesis. J Exp Clin Cancer Res. 2020;39(1):204.

[146] Gonzalez-MorenoO, Lecanda J, GreenJE, et al. VEGF elicits epithelial-mesenchymal transition (EMT) in prostate intraepithelial neoplasia (PIN)-like cells via an autocrine loop. Exp Cell Res. 2010;316(4):554-567.

[147] VogiatzoglouAP, SpanouS, SachiniN, et al. Promyelocytic leukemia protein regulates angiogenesis and epithelial-mesenchymal transition to limit metastasis in MDA-MB-231 breast cancer cells. Mol Oncol. 2023;17(10):2090-2108.

[148] XiongX, YuanL, YangK, Wang X. The HIFIA/LINC02913/IGF1R axis promotes the cell function of adipose-derived mesenchymal stem cells under hypoxia via activating the PI3K/AKT pathway. J Transl Med. 2023;21(1):732.

[149] NeeliPK, SahooS, KarnewarS, et al. DOT1L regulates MTDH-mediated angiogenesis in triple-negative breast cancer: intermediacy of NF-κB-HIF1αaxis. FEBS J. 2023;290(2):502-520.

[150] RenR, MaK, JiangY, et al. Endothelial miR-196b-5p regulates angiogenesis via the hypoxia/miR-196b-5p/HMGA2/HIF1αloop. Am J Physiol Cell Physiol. 2023;324(2):C407-C419.

[151] PangL, Dunterman M, XuanW, et al. Circadian regulator CLOCK promotes tumor angiogenesis in glioblastoma. Cell Rep. 2023;42(2):112127.

[152] ArunachalamA, Lakshmanan DK, RavichandranG, et al. Regulatory mechanisms of heme regulatory protein BACH1: a potential therapeutic target for cancer. Med Oncol. 2021;38(10):122.

[153] DuvigneauJC, Esterbauer H, KozlovAV. Role of heme oxygenase as a modulator of heme-mediated pathways. Antioxidants. 2019;8(10):475.

[154] ShimizuT, Lengalova A, MartínekV, MartínkováM. Heme: emergent roles of heme in signal transduction, functional regulation and as catalytic centres. Chem Soc Rev. 2019;48(24):5624-5657.

[155] OgawaK. Heme mediates derepression of Maf recognition element through direct binding to transcription repressor Bach1. EMBO J. 2001;20(11):2835-2843.

[156] WangT, Ashrafi A, ModareszadehP, et al. An analysis of the multifaceted roles of heme in the pathogenesis of cancer and related diseases. Cancers. 2021;13(16):4142.

[157] LignittoL, LeBoeuf SE, HomerH, et al. Nrf2 activation promotes lung cancer metastasis by inhibiting the degradation of bach1. Cell. 2019;178(2):316-329.e18.

[158] Zenke-KawasakiY, DohiY, KatohY, et al. Heme induces ubiquitination and degradation of the transcription factor Bach1. Mol Cell Biol. 2007;27(19):6962-6971.

[159] LeeJ, Yesilkanal AE, WynneJP, et al. Effective breast cancer combination therapy targeting BACH1 and mitochondrial metabolism. Nature. 2019;568(7751):254-258.

[160] LiuZ, WangJ, ChenH, et al. Uncovering BTB and CNC homology1 (BACH1) as a novel cancer therapeutic target. Front Genet. 2022;13:920911.

[161] AletahaM, Mansoori B, MohammadiA, FazeliM, Baradaran B. Therapeutic effects of bach1 siRNA on human breast adenocarcinoma cell line. Biomed Pharmacother. 2017;88:34-42.

[162] SatoM, Matsumoto M, SaikiY, et al. BACH1 promotes pancreatic cancer metastasis by repressing epithelial genes and enhancing epithelial-mesenchymal transition. Cancer Res. 2020;80(6):1279-1292.

[163] HanW, ZhangY, NiuC, et al. BTB and CNC homology 1 (Bach1) promotes human ovarian cancer cell metastasis by HMGA2-mediated epithelial-mesenchymal transition. Cancer Lett. 2019;445:45-56.

[164] LiangY, WuH, LeiR, et al. Transcriptional network analysis identifies BACH1 as a master regulator of breast cancer bone metastasis. J Biol Chem. 2012;287(40):33533-33544.

[165] XieM, SunM, JiX, et al. Overexpression of BACH1 mediated by IGF2 facilitates hepatocellular carcinoma growth and metastasis via IGF1R and PTK2. Theranostics. 2022;12(3):1097-1116.

[166] TakemotoK, Kobatake K, MiuraK, et al. BACH1 promotes clear cell renal cell carcinoma progression by upregulating oxidative stress-related tumorigenicity. Cancer Sci. 2023;114(2):436-448.

[167] ShajariN, Davudian S, KazemiT, et al. Silencing of BACH1 inhibits invasion and migration of prostate cancer cells by altering metastasis-related gene expression. Artif Cells Nanomed Biotechnol. 2018;46(7):1495-1504.

[168] DavudianS, Shajari N, KazemiT, et al. BACH1 silencing by siRNA inhibits migration of HT-29 colon cancer cells through reduction of metastasis-related genes. Biomed Pharmacother. 2016;84:191-198.

[169] NiuC, WangS, GuoJ, et al. BACH1 recruits NANOG and histone H3 lysine 4 methyltransferase MLL/SET1 complexes to regulate enhancer-promoter activity and maintains pluripotency. Nucleic Acids Res. 2021;49(4):1972-1986.

[170] JiangP, LiF, LiuZ, HaoS, GaoJ, LiS. BTB and CNC homology 1 (Bach1) induces lung cancer stem cell phenotypes by stimulating CD44 expression. Respir Res. 2021;22(1):320.

[171] MansooriB, Mohammadi A, AsadzadehZ, et al. HMGA2 and Bach-1 cooperate to promote breast cancer cell malignancy. J Cell Physiol. 2019;234(10):17714-17726.

[172] WangC, ZhangL, CaoM, et al. Thioredoxin facilitates hepatocellular carcinoma stemness and metastasis by increasing BACH1 stability to activate the AKT/mTOR pathway. FASEB J. 2023;37(6):e22943.

[173] HaoS, ZhuX, LiuZ, et al. Chronic intermittent hypoxia promoted lung cancer stem cell-like properties via enhancing Bach1 expression. Respir Res. 2021;22(1):58.

[174] WangT, DongY, HuangZ, et al. Antioxidants stimulate BACH1-dependent tumor angiogenesis. J Clin Invest. 2023;133(20):e169671.

[175] CohenB, Tempelhof H, RazT, et al. BACH family members regulate angiogenesis and lymphangiogenesis by modulating VEGFC expression. Life Sci Alliance. 2020;3(4):e202000666.

[176] MoonEJ, MelloSS, LiCG, et al. The HIF target MAFF promotes tumor invasion and metastasis through IL11 and STAT3 signaling. Nat Commun. 2021;12(1):4308.

[177] HuangX, ZhengJ, LiJ, et al. Functional role of BTB and CNC homology 1 gene in pancreatic cancer and its association with survival in patients treated with gemcitabine. Theranostics. 2018;8(12):3366-3379.

[178] JiangL, YinM, WeiX, et al. Bach1 represses Wnt/β-catenin signaling and angiogenesis. Circ Res. 2015;117(4):364-375.

[179] MorganMJ, LiuZ. Crosstalk of reactive oxygen species and NF-κB signaling. Cell Res. 2011;21(1):103-115.

[180] GuoQ, JinY, ChenX, et al. NF-κB in biology and targeted therapy: new insights and translational implications. Signal Transduct Target Ther. 2024;9(1):53.

[181] PerkinsND. The diverse and complex roles of NF-κB subunits in cancer. Nat Rev Cancer. 2012;12(2):121-132.

[182] KendellenMF, Bradford JW, LawrenceCL, ClarkKS, Baldwin AS. Canonical and non-canonical NF-κB signaling promotes breast cancer tumor-initiating cells. Oncogene. 2014;33(10):1297-1305.

[183] DrainAP, ZahirN, NortheyJJ, et al. Matrix compliance permits NF-κB activation to drive therapy resistance in breast cancer. J Exp Med. 2021;218(5):e20191360.

[184] KeX, YangC, ChengW, Yang YY. Delivery of NF-κB shRNA using carbamate-mannose modified PEI for eliminating cancer stem cells. Nanomed Nanotechnol Biol Med. 2018;14(2):405-414.

[185] MarquardtJU, RaggiC, AndersenJB, et al. Human hepatic cancer stem cells are characterized by common stemness traits and diverse oncogenic pathways. Hepatology. 2011;54(3):1031-1042.

[186] MarquardtJU, Gomez-Quiroz L, Arreguin CamachoLO, et al. Curcumin effectively inhibits oncogenic NF-κB signaling and restrains stemness features in liver cancer. J Hepatol. 2015;63(3):661-669.

[187] WangD, FuL, SunH, GuoL, DuBoisRN. Prostaglandin E2 promotes colorectal cancer stem cell expansion and metastasis in mice. Gastroenterology. 2015;149(7):1884-1895.e4.

[188] SmithHA, KangY. The metastasis-promoting roles of tumor-associated immune cells. J Mol Med. 2013;91(4):411-429.

[189] ZhangL, WangD, LiY, et al. CCL21/CCR7 axis contributed to CD133+pancreatic cancer stem-Like cell metastasis via EMT and Erk/NF-κB pathway. PLoS One. 2016;11(8):e0158529.

[190] WangX, WangC, ZhangX, et al. Bmi-1 regulates stem cell-like properties of gastric cancer cells via modulating miRNAs. J Hematol Oncol. 2016;9(1):90.

[191] LiB, LuY, YuL, et al. miR-221/222 promote cancer stem-like cell properties and tumor growth of breast cancer via targeting PTEN and sustained Akt/NF-κB/COX-2 activation. Chemico-Biol Interact. 2017;277:33-42.

[192] TothovaZ, Kollipara R, HuntlyBJ, et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell. 2007;128(2):325-339.

[193] YalcinS, Marinkovic D, MungamuriSK, et al. ROS-mediated amplification of AKT/mTOR signalling pathway leads to myeloproliferative syndrome in Foxo3(-/-) mice. EMBO J. 2010;29(24):4118-4131.

[194] SmithJ, LadiE, Mayer-PröschelM, NobleM. Redox state is a central modulator of the balance between self-renewal and differentiation in a dividing glial precursor cell. Proc Natl Acad Sci. 2000;97(18):10032-10037.

[195] ItoK, HiraoA, AraiF, et al. Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nature Med. 2006;12(4):446-451.

[196] MiyamotoK, ArakiKY, NakaK, et al. Foxo3a is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell. 2007;1(1):101-112.

[197] NakaK, HoshiiT, MuraguchiT, et al. TGF-β-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. Nature. 2010;463(7281):676-680.

[198] TenbaumSP, Ordóñez-Morán P, PuigI, et al. β-catenin confers resistance to PI3K and AKT inhibitors and subverts FOXO3a to promote metastasis in colon cancer. Nature Med. 2012;18(6):892-901.

[199] PrabhuVV, AllenJE, DickerDT, El-Deiry WS. Small-molecule ONC201/TIC10 targets chemotherapy-resistant colorectal cancer stem-like cells in an Akt/Foxo3a/TRAIL-dependent manner. Cancer Res. 2015;75(7):1423-1432.

[200] SalcherS, SpodenG, HagenbuchnerJ, et al. A drug library screen identifies carbenoxolone as novel FOXO inhibitor that overcomes FOXO3-mediated chemoprotection in high-stage neuroblastoma. Oncogene. 2020;39(5):1080-1097.

[201] HanC-Y, ChoK-B, ChoiH-S, Han H-K, KangK-W. Role of FoxO1 activation in MDR1 expression in adriamycin-resistant breast cancer cells. Carcinogenesis. 2008;29(9):1837-1844.

[202] GotoT, TakanoM, HirataJ, Tsuda H. The involvement of FOXO1 in cytotoxic stress and drug-resistance induced by paclitaxel in ovarian cancers. Br J Cancer. 2008;98(6):1068-1075.

[203] ShaulianE. AP-1-he Jun proteins: oncogenes or tumor suppressors in disguise? Cellular Signalling. 2010;22(6):894-899.

[204] BejjaniF, EvannoE, ZibaraK, Piechaczyk M, Jariel-EncontreI. The AP-1 transcriptional complex: local switch or remote command? Biochim Biophys Acta Rev Cancer. 2019;1872(1):11-23.

[205] TewariD, NabaviSF, NabaviSM, et al. Targeting activator protein 1 signaling pathway by bioactive natural agents: possible therapeutic strategy for cancer prevention and intervention. Pharmacol Res. 2018;128:366-375.

[206] GazonH, Barbeau B, MesnardJ-M, PeloponeseJ-M. Hijacking of the AP-1 signaling pathway during development of ATL. Front Microbiol. 2018;8:2686.

[207] GrigoriadisA, Schellander K, WangZ, WagnerE. Osteoblasts are target cells for transformation in c-fos transgenic mice. J Cell Biol. 1993;122(3):685-701.

[208] LiuY, LuC, ShenQ, Munoz-Medellin D, KimH, BrownPH. AP-1 blockade in breast cancer cells causes cell cycle arrest by suppressing G1 cyclin expression and reducing cyclin-dependent kinase activity. Oncogene. 2004;23(50):8238-8246.

[209] TolzaC, Bejjani F, EvannoE, et al. AP-1 signaling by Fra-1 directly regulates HMGA1 oncogene transcription in Triple-negative breast cancers. Mol Cancer Res. 2019;17(10):1999-2014.

[210] ToullecA, GeraldD, DespouyG, et al. Oxidative stress promotes myofibroblast differentiation and tumour spreading. EMBO Mol Med. 2010;2(6):211-230.

[211] ShaoL, YuH, WangM, et al. DKK1-SE recruits AP1 to activate the target gene DKK1 thereby promoting pancreatic cancer progression. Cell Death Dis. 2024;15(8):566.

[212] WangZ, Townley SL, ZhangS, et al. FOXA2 rewires AP-1 for transcriptional reprogramming and lineage plasticity in prostate cancer. Nat Commun. 2024;15(1):4914.

[213] DurandS, TangY, PommierRM, et al. ZEB1 controls a lineage-specific transcriptional program essential for melanoma cell state transitions. Oncogene. 2024;43(20):1489-1505.

[214] KleffelS, Schatton T. Tumor dormancy and cancer stem cells: two sides of the same coin? Adv Exp Med Biol. 2013;734:145.

[215] HenO, BarkanD. Dormant disseminated tumor cells and cancer stem/progenitor-like cells: similarities and opportunities. Sem Cancer Biol. 2020;60:157-165.

[216] KleinCA. Framework models of tumor dormancy from patient-derived observations. Curr Opin Genet Dev. 2011;21(1):42-49.

[217] SosaMS, Bragado P, Aguirre-GhisoJA. Mechanisms of disseminated cancer cell dormancy: an awakening field. Nat Rev Cancer. 2014;14(9):611-622.

[218] YehAC, Ramaswamy S. Mechanisms of cancer cell Dormancy-another Hallmark of cancer? Cancer Res. 2015;75(23):5014-5022.

[219] AlvarezJV, PanT, RuthJ, et al. Par-4 downregulation promotes breast cancer recurrence by preventing multinucleation following targeted therapy. Cancer Cell. 2013;24(1):30-44.

[220] WalensA, DiMarco AV, LupoR, KrogerBR, Damrauer JS, AlvarezJV. CCL5 promotes breast cancer recurrence through macrophage recruitment in residual tumors. eLife. 2019;8:e43653.

[221] FengY, PanT-C, PantDK, et al. SPSB1 promotes breast cancer recurrence by potentiating c-MET signaling. Cancer Discovery. 2014;4(7):790-803.

[222] FoxDB, GarciaNMG, McKinneyBJ, et al. NRF2 activation promotes the recurrence of dormant tumour cells through regulation of redox and nucleotide metabolism. Nat Metab. 2020;2(4):318-334.

[223] LeungHW, LauEYT, LeungCON, et al. NRF2/SHH signaling cascade promotes tumor-initiating cell lineage and drug resistance in hepatocellular carcinoma. Cancer Lett. 2020;476:48-56.

[224] WakabayashiN, Chartoumpekis DV, KenslerTW. Crosstalk between Nrf2 and notch signaling. Free Radic Biol Med. 2015;88(Pt B):158-167.

[225] PopovaSA, Buczacki SJA. Itraconazole perturbs colorectal cancer dormancy through SUFU-mediated WNT inhibition. Mol Cell Oncol. 2018;5(4):e1494950.

[226] RenD, DaiY, YangQ, et al. Wnt5a induces and maintains prostate cancer cells dormancy in bone. J Exp Med. 2019;216(2):428-449.

[227] YamadaKM, Collins JW, Cruz WalmaDA, et al. Extracellular matrix dynamics in cell migration, invasion and tissue morphogenesis. Int J Exp Pathol. 2019;100(3):144-152.

[228] WatsonWH, Ritzenthaler JD, RomanJ. Lung extracellular matrix and redox regulation. Redox Biol. 2016;8:305-315.

[229] JiangJ, WangK, ChenY, Chen H, NiceEC, HuangC. Redox regulation in tumor cell epithelial-mesenchymal transition: molecular basis and therapeutic strategy. Signal Transduct Target Ther. 2017;2:17036.

[230] WeiJ, HuM, HuangK, Lin S, DuH. Roles of proteoglycans and glycosaminoglycans in cancer development and progression. Int J Mol Sci. 2020;21(17):5983.

[231] ChanmeeT, OntongP, KimataK, Itano N. Key roles of hyaluronan and its CD44 receptor in the stemness and survival of cancer stem cells. Front Oncol. 2015;5:180.

[232] OhtaY, FujiiM, TakahashiS, et al. Cell-matrix interface regulates dormancy in human colon cancer stem cells. Nature. 2022;608(7924):784-794.

[233] ZhaoL, KangM, LiuX, et al. UBR7 inhibits HCC tumorigenesis by targeting Keap1/Nrf2/Bach1/HK2 and glycolysis. J Exp Clin Cancer Res. 2022;41(1):330.

[234] BiZ, ZhangQ, FuY, et al. Nrf2 and HIF1αconverge to arsenic-induced metabolic reprogramming and the formation of the cancer stem-like cells. Theranostics. 2020;10(9):4134-4149.

[235] LuY, WangB, ShiQ, WangX, WangD, Zhu L. Brusatol inhibits HIF-1 signaling pathway and suppresses glucose uptake under hypoxic conditions in HCT116 cells. Sci Rep. 2016;6:39123.

[236] LimS, LiuH, da SilvaLM, et al. Immunoregulatory protein B7-H3 reprograms glucose metabolism in cancer cells by ROS-mediated stabilization of HIF1α. Cancer Res. 2016;76(8):2231-2242.

[237] JiJ, LvJ, LvM, et al. USP14 regulates heme metabolism and ovarian cancer invasion through BACH1 deubiquitination and stabilization. Biochem Biophys Res Commun. 2023;667:186-193.

[238] ZhangH-S, ZhangZ-G, DuG-Y, et al. Nrf2 promotes breast cancer cell migration via up-regulation of G6PD/HIF-1α/Notch1 axis. J Cell Mol Med. 2019;23(5):3451-3463.

[239] KimT-H, HurE, KangS-J, et al. NRF2 blockade suppresses colon tumor angiogenesis by inhibiting hypoxia-induced activation of HIF-1α. Cancer Res. 2011;71(6):2260-2275.

[240] ParveenSMA, NataniS, Sruthi K.K.KK, KhilarP, Ummanni R. HIF-1αand Nrf2 regulates hypoxia induced overexpression of DDAH1 through promoter activation in prostate cancer. Int J Biochem Cell Biol. 2022;147:106232.

[241] BhardwajV, HeJ. Reactive oxygen species, metabolic plasticity, and drug resistance in cancer. Int J Mol Sci. 2020;21(10):3412.

[242] Martins-NevesSR, Paiva-Oliveira DI, Wijers-KosterPM, et al. Chemotherapy induces stemness in osteosarcoma cells through activation of Wnt/β-catenin signaling. Cancer Lett. 2016;370(2):286-295.

[243] MaiY, SuJ, YangC, Xia C, FuL. The strategies to cure cancer patients by eradicating cancer stem-like cells. Mol Cancer. 2023;22(1):171.

[244] JuF, AtyahMM, HorstmannN, et al. Characteristics of the cancer stem cell niche and therapeutic strategies. Stem Cell Res Ther. 2022;13(1):233.

[245] MinH-Y, LeeH-Y. Cellular dormancy in cancer: mechanisms and potential targeting strategies. Cancer Res Treatment. 2023;55(3):720-736.

[246] SiY, HuiC, GuoT, et al. Phellodendronoside A exerts anticancer effects depending on inducing apoptosis through ROS/Nrf2/Notch pathway and modulating metabolite profiles in hepatocellular carcinoma. J Hepatocell Carcinoma. 2023;10:935-948.

[247] OuyangW-C, LiaoY-W, ChenP-N, Lu K-H, YuC-C, HsiehP-L. Hinokitiol suppresses cancer stemness and oncogenicity in glioma stem cells by Nrf2 regulation. Cancer Chemother Pharmacol. 2017;80(2):411-419.

[248] FouzderC, Mukhuty A, MukherjeeS, MalickC, KunduR. Trigonelline inhibits Nrf2 via EGFR signalling pathway and augments efficacy of cisplatin and etoposide in NSCLC cells. Toxicol In Vitro. 2021;70:105038.

[249] RenD, Villeneuve NF, JiangT, et al. Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism. Proc Natl Acad Sci. 2011;108(4):1433-1438.

[250] FanQ, LiangX, XuZ, et al. Pedunculoside inhibits epithelial-mesenchymal transition and overcomes gefitinib-resistant non-small cell lung cancer through regulating MAPK and Nrf2 pathways. Phytomedicine. 2023;116:154884.

[251] CucciMA, Grattarola M, DianzaniC, et al. Ailanthone increases oxidative stress in CDDP-resistant ovarian and bladder cancer cells by inhibiting of Nrf2 and YAP expression through a post-translational mechanism. Free Radic Biol Med. 2020;150:125-135.

[252] BaoB, AhmadA, KongD, et al. Hypoxia induced aggressiveness of prostate cancer cells is linked with deregulated expression of VEGF, IL-6 and miRNAs that are attenuated by CDF. PLoS One. 2012;7(8):e43726.

[253] ZuoJ, GuoY, PengX, et al. Inhibitory action of pristimerin on hypoxia-mediated metastasis involves stem cell characteristics and EMT in PC-3 prostate cancer cells. Oncol Rep. 2015;33(3):1388-1394.

[254] WangW-J, SuiH, QiC, et al. Ursolic acid inhibits proliferation and reverses drug resistance of ovarian cancer stem cells by downregulating ABCG2 through suppressing the expression of hypoxia-inducible factor-1αin vitro. Oncol Rep. 2016;36(1):428-440.

[255] ZhangH, QianDZ, TanYS, et al. Digoxin and other cardiac glycosides inhibit HIF-1αsynthesis and block tumor growth. Proc Natl Acad Sci. 2008;105(50):19579-19586.

[256] KawaharaTLA, Michishita E, AdlerAS, et al. SIRT6 links histone H3 lysine 9 deacetylation to NF-κB-dependent gene expression and organismal life span. Cell. 2009;136(1):62-74.

[257] KasparJW, Jaiswal AK. Antioxidant-induced phosphorylation of tyrosine 486 leads to rapid nuclear export of Bach1 that allows Nrf2 to bind to the antioxidant response element and activate defensive gene expression. J Biol Chem. 2010;285(1):153-162.

[258] MasoudGN, LiW. HIF-1αpathway: role, regulation and intervention for cancer therapy. Acta Pharm Sin B. 2015;5(5):378-389.

[259] Karami FathM, Garousi S, MottahediM, et al. The role of hypoxia-inducible factors in breast cancer stem cell specification. Pathol Res Pract. 2023;243:154349.

[260] DanieleS, Zappelli E, NataliL, MartiniC, Trincavelli ML. Modulation of A1 and A2B adenosine receptor activity: a new strategy to sensitise glioblastoma stem cells to chemotherapy. Cell Death Dis. 2014;5(11):e1539.

[261] CheloniG, Tanturli M, TusaI, et al. Targeting chronic myeloid leukemia stem cells with the hypoxia-inducible factor inhibitor acriflavine. Blood. 2017;130(5):655-665.

[262] PadillaJ, LeeJ. A novel therapeutic target, BACH1, regulates cancer metabolism. Cells. 2021;10(3):634.

[263] LuoM, ShenN, ShangL, et al. Simultaneous targeting of NQO1 and SOD1 eradicates breast cancer stem cells via mitochondrial futile redox cycling. Cancer Res. Published online September 12, 2024.

[264] ChoJ-M, Manandhar S, LeeH-R, ParkH-M, KwakM-K. Role of the Nrf2-antioxidant system in cytotoxicity mediated by anticancer cisplatin: implication to cancer cell resistance. Cancer Lett. 2008;260(1-2):96-108.

[265] ZhangP, SinghA, YegnasubramanianS, et al. Loss of Kelch-like ECH-associated protein 1 function in prostate cancer cells causes chemoresistance and radioresistance and promotes tumor growth. Mol Cancer Ther. 2010;9(2):336-346.

[266] ShenX, ZhaoY, LiuG, et al. Upregulation of programmed death ligand 1 by liver kinase B1 and its implication in programmed death 1 blockade therapy in non-small cell lung cancer. Life Sci. 2020;256:117923.

[267] SinghA, DaemenA, NicklesD, et al. NRF2 activation promotes aggressive lung cancer and associates with poor clinical outcomes. Clin Cancer Res. 2021;27(3):877-888.

[268] LiY, GaoX, NiC, ZhaoB, ChengX. The application of patient-derived organoid in the research of lung cancer. Cell Oncol. 2023;46(3):503-519.

RIGHTS & PERMISSIONS

2024 2024 The Author(s). MedComm – Oncology published by John Wiley & Sons Australia, Ltd on behalf of Sichuan International Medical Exchange & Promotion Association (SCIMEA).