Hypoxia-inducible factors: A target of cancer treatment

Abstract

Hypoxia, a characteristic of the tumor microenvironment caused by abnormal blood vessels and rapid cellular growth, enhances tumor aggressiveness and leads to resistance against conventional therapies. Unlike normal cells, hypoxic tumor cells activate adaptive survival mechanisms, prominently mediated by hypoxia-inducible factors (HIFs). HIF-1α is the most studied member of the HIF family, and the stability of its alpha subunit (HIF-1α) is a crucial determinant of the overall activity of the HIF-1α complex. HIF-1α stabilization under low oxygen occurs via oxygen-dependent and oxygen-independent pathways: in the oxygen-dependent pathway, HIf-1α is normally degraded by the von Hippel-Lindau protein (pVHL) when oxygen is present. Under hypoxia, hydroxylation is inhibited, allowing HIF-1α to accumulate. In the oxygen-independent pathway, growth factor signals activate cascades like PI3K/Akt/mTOR and MAPK/ERK, stabilizing HIF-1α regardless of oxygen levels. Stabilized HIF-1α translocates to the nucleus, promoting transcription of proangiogenic genes such as vascular endothelial growth factor (VEGF), thereby facilitating angiogenesis, tumor invasion, and progression. Dysregulation of these signaling pathways underpins the pathogenesis of many cancers, making HIF and its associated cascades critical targets for innovative cancer therapies. This review focuses on the pivotal role of HIF in tumor angiogenesis and emphasizes the therapeutic potential of targeting HIF signaling in cancer treatment.

Keywords

Cancer angiogenesis / Cancer therapy / Hypoxia-inducible factors / Mitogen-activated protein kinase / Phosphatidyli-nositol 3-kinase

References

[1] Semenza GL. HIF-1 and human disease: one highly involved fac- tor. Genes & Development. 2000; 14(16): 1983-1991. https://doi.org/10.1101/gad.14.16.1983

[2] Burton GJ, Cindrova-Davies T, Yung HW, et al. Hypoxia and re- productive health: Oxygen and development of the human pla- centa. Reproduction. 2021; 161(1): F53-F65. PMid: 32438347. https://doi.org/10.1530/REP-20-0153

[3] Godet I, Doctorman S, Wu F, et al. Detection of hypoxia in cancer models: significance, challenges, and advances. Cells. 2022; 11(4): 686. PMid: 35203334. https://doi.org/10.3390/cells11040686

[4] Zhou S, Sun J, Zhu W, et al. Hypoxia studies in non small cell lung cancer: Pathogenesis and clinical implications. Oncology Reports. 2025; 53(2): 29. PMid: 39749693. https://doi.org/10.3892/or.2024.8862

[5] Zheng X, Wang X, Mao H, et al. Hypoxia-specific ultrasensitive detection of tumors and cancer cells in vivo. Nature Communications. 2015; 6(1): 5834. PMid: 25556360. https://doi.org/10.1038/ncomms6834

[6] Wang GL, Semenza GL. Purification and characterization of hypoxia- inducible factor 1 (*). Journal of Biological Chemistry. 1995; 270(3):1230-1237. PMid: 7836384. https://doi.org/10.1074/jbc.270.3.1230

[7] Harris AL. Hypoxia-a key regulatory factor in tumour growth. Na- ture Reviews Cancer. 2002; 2(1): 38-47. PMid: 11902584. https://doi.org/10.1038/nrc704

[8] Kobayashi S, Kawaguchi H, Shirai T, et al. Automatic redirection of carbon flux between glycolysis and pentose phosphate pathway using an oxygen-responsive metabolic switch in Corynebacterium glutamicum. ACS Synthetic Biology. 2020; 9(4): 814-826. PMid: 32202411. https://doi.org/10.1021/acssynbio.9b00493

[9] Zimna A, Kurpisz M. Hypoxia-inducible factor-1 in physiologi- cal and pathophysiological angiogenesis: applications and thera- pies. BioMed Research International. 2015; 2015: 549412. PMid: 26146622. https://doi.org/10.1155/2015/549412

[10] Qin Q, Liu H, Shou Jn, et al. The inhibitor effect of RKIP on inflam- masome activation and inflammasome-dependent diseases. Cellular & Molecular Immunology. 2021; 18(4): 992-1004. PMid: 32901127. https://doi.org/10.1038/s41423-020-00525-3

[11] Semenza GL. Hypoxia-inducible factor 1: oxygen homeostasis and disease pathophysiology. Trends in Molecular Medicine. 2001; 7(8): 345-350. PMid: 11516994. https://doi.org/10.1016/S1471-4914(01)02090-1

[12] Yfantis A, Mylonis I, Chachami G, et al. Transcriptional response to hypoxia: The role of HIF-1-associated co-regulators. Cells. 2023; 12(5): 798. PMid: 36899934. https://doi.org/10.3390/cells12050798

[13] Madan E, Parker TM, Pelham CJ, et al. HIF-transcribed p 53 chaper- ones HIF-1α. Nucleic Acids Research. 2019; 47(19): 10212-10234. PMid: 31538203. https://doi.org/10.1093/nar/gkz766

[14] Min JH, Yang H, Ivan M, et al. Structure of an HIF-1α-pVHL complex: hydroxyproline recognition in signaling. Science. 2002; 296(5574): 1886-1889. PMid: 12004076. https://doi.org/10.1126/science.1073440

[15] Levy AP, Levy NS, Iliopoulos O, et al. Regulation of vascular en- dothelial growth factor by hypoxia and its modulation by the von Hippel-Lindau tumor suppressor gene. Kidney International. 1997; 51(2): 575-578. PMid: 9027742. https://doi.org/10.1038/ki.1997.82

[16] He W, Batty-Stuart S, Lee JE, Ohh M. HIF-1α hydroxyprolines modulate oxygen-dependent protein stability via single VHL in- terface with comparable effect on ubiquitination rate. Journal of Molecular Biology. 2021; 433(22): 167244. PMid: 34537235. https://doi.org/10.1016/j.jmb.2021.167244

[17] BelAiba RS, Bonello S, Zähringer C, et al. Hypoxia up-regulates hypoxia-inducible factor-1α transcription by involving phosphatidyli- nositol 3-kinase and nuclear factor κB in pulmonary artery smooth muscle cells. Molecular Biology of the Cell. 2007; 18(12): 4691-4697. PMid: 17898080. https://doi.org/10.1091/mbc.e07-04-0391

[18] Kim CH, Cho YS, Chun YS, et al. Early expression of myocar- dial HIF-1α in response to mechanical stresses: regulation by stretch-activated channels and the phosphatidylinositol 3-kinase signaling pathway. Circulation Research. 2002; 90(2): e25-e33. https://doi.org/10.1161/hh0202.104923

[19] Dong S, Liang S, Cheng Z, et al. ROS/PI3K/Akt and Wnt/β-catenin signalings activate HIF-1α-induced metabolic reprogramming to impart 5-fluorouracil resistance in colorectal cancer. Journal of Ex- perimental & Clinical Cancer Research. 2022; 41(1): 1-27. PMid: 34998404. https://doi.org/10.1186/s13046-021-02229-6

[20] Agani F, Jiang BH. Oxygen-independent regulation of HIF-1: novel involvement of PI3K/AKT/mTOR pathway in cancer. Current Can- cer Drug Targets. 2013; 13(3): 245-251. PMid: 23297826. https://doi.org/10.2174/1568009611313030003

[21] Marzo F, Lavorgna A, Coluzzi G, et al. Erythropoietin in heart and vessels: focus on transcription and signalling pathways. Journal of Thrombosis and Thrombolysis. 2008; 26: 183-187. PMid: 18338108. https://doi.org/10.1007/s11239-008-0212-3

[22] Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia: role of the HIF system. Nature Medicine. 2003; 9(6): 677-684. PMid: 12778166. https://doi.org/10.1038/nm0603-677

[23] Manuelli V, Pecorari C, Filomeni G, et al. Regulation of redox sig- naling in HIF-1-dependent tumor angiogenesis. The FEBS Journal. 2022; 289(18): 5413-5425. PMid: 34228878. https://doi.org/10.1111/febs.16110

[24] Hockel M, Vaupel P. Tumor hypoxia: definitions and current clin- ical, biologic, and molecular aspects. Journal of the National Can- cer Institute. 2001; 93(4): 266-276. PMid: 11181773. https://doi.org/10.1093/jnci/93.4.266

[25] Wu Q, Zhou W, Yin S, et al. Blocking triggering receptor expressed on myeloid cells-1-positive tumor-associated macrophages induced by hypoxia reverses immunosuppression and anti-programmed cell death ligand 1 resistance in liver cancer. Hepatology. 2019; 70(1): 198-214. PMid: 30810243. https://doi.org/10.1002/hep.30593

[26] Prabhakar NR, Semenza GL.Adaptive and maladaptive cardiores- piratory responses to continuous and intermittent hypoxia mediated by hypoxia-inducible factors 1 and 2. Physiological Reviews. 2012; 92(3): 967-1003. PMid: 22811423. https://doi.org/10.1152/physrev.00030.2011

[27] Wood SM, Gleadle JM, Pugh CW, et al. The role of the aryl hydro- carbon receptor nuclear translocator (ARNT) in hypoxic induction of gene expression: studies in ARNT-deficient cells. Journal of Bi- ological Chemistry. 1996; 271(25): 15117-15123. PMid: 8662957. https://doi.org/10.1074/jbc.271.25.15117

[28] Ramirez-Rincón CL. Role of the hypoxia-inducible factor (HIF) in the process of neurogenesis at the hippocampal level. Revista Mexi- cana de Neurociencia. 2022; 23(2): 71-77. https://doi.org/10.24875/RMN.21000020

[29] Chen S, Sang N. Hypoxia-inducible factor-1: a critical player in the survival strategy of stressed cells. Journal of Cellular Biochemistry. 2016; 117(2): 267-278. PMid: 26206147. https://doi.org/10.1002/jcb.25283

[30] Hellwig-Bürgel T, Stiehl DP, Wagner AE, et al. hypoxia-inducible factor-1 (HIF-1): a novel transcription factor in immune reactions. Journal of Interferon & Cytokine Research. 2005; 25(6): 297-310. PMid: 15957953. https://doi.org/10.1089/jir.2005.25.297

[31] Jiang BH, Rue E, Wang GL, et al. Dimerization,DNA binding, and transactivation properties of hypoxia-inducible factor 1. Journal of Biological Chemistry. 1996; 271(30): 17771-17778. PMid: 8663540. https://doi.org/10.1074/jbc.271.30.17771

[32] Ivan M, Kondo K, Yang H, et al. HIFα targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sens- ing. Science. 2001; 292(5516): 464-468. PMid: 11292862. https://doi.org/10.1126/science.1059817

[33] Jaakkola P, Mole DR, Tian YM, et al. Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 2001; 292(5516): 468-472. PMid: 11292861. https://doi.org/10.1126/science.1059796

[34] Iyer NV, Leung SW, Semenza GL. The human hypoxia-inducible factor 1α gene: Hif1astructure and evolutionary conservation. Ge- nomics. 1998; 52(2): 159-165. PMid: 9782081. https://doi.org/10.1006/geno.1998.5416

[35] Huang LE, Gu J, Schau M, et al.Regulation of hypoxia-inducible factor 1α is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway. Proceedings of the National Academy of Sciences. 1998; 95(14): 7987-7992. PMid: 9653127. https://doi.org/10.1073/pnas.95.14.7987

[36] Lando D, Peet DJ, Gorman JJ, et al. FIH-1 is an asparaginyl hydrox- ylase enzyme that regulates the transcriptional activity of hypoxia- inducible factor. Genes & Development. 2002; 16(12): 1466-1471. PMid: 12080085. https://doi.org/10.1101/gad.991402

[37] Pugh CW, O’Rourke JF, Nagao M, et al. Activation of hypoxia- inducible factor-1; definition of regulatory domains within the α subunit. Journal of Biological Chemistry. 1997; 272(17): 11205-11214. PMid: 9111021. https://doi.org/10.1074/jbc.272.17.11205

[38] Jiang BH, Zheng JZ, Leung SW, et al. Transactivation and in- hibitory domains of hypoxia-inducible factor 1α: modulation of transcriptional activity by oxygen tension. Journal of Biological Chemistry. 1997; 272(31): 19253-19260. PMid: 9235919. https://doi.org/10.1074/jbc.272.31.19253

[39] Soni S, Padwad YS. HIF-1 in cancer therapy: two decade long story of a transcription factor. Acta Oncologica. 2017; 56(4): 503-515. PMid: 28358664. https://doi.org/10.1080/0284186X.2017.1301680

[40] Kallio PJ, Pongratz I, Gradin K, et al.Activation of hypoxia-inducible factor 1α:posttranscriptional regulation and conformational change by recruitment of the Arnt transcription factor. Proceedings of the National Academy of Sciences. 1997; 94(11): 5667-5672. PMid: 9159130. https://doi.org/10.1073/pnas.94.11.5667

[41] Cramer T, Vaupel P. Is tissue hypoxia the principal mechanism for immune evasion and malignant progression in hepatocellular carcinoma? Journal of Hepatology. 2021; 75(3): 735-736. PMid: 33839193. https://doi.org/10.1016/j.jhep.2021.03.024

[42] Salceda S, Caro J. Hypoxia-inducible factor 1α (HIF-1α) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions: its stabilization by hypoxia depends on redox-induced changes. Journal of Biological Chemistry. 1997; 272(36): 22642-22647. PMid: 9278421. https://doi.org/10.1074/jbc.272.36.22642

[43] Daly LA, Brownridge PJ, Batie M, et al. Oxygen-dependent changes in binding partners and post-translational modifications regulate the abundance and activity of HIF-1α/2α. Science Signaling. 2021; 14(692): eabf6685. PMid: 34285132. https://doi.org/10.1126/scisignal.abf6685

[44] Iwai K, Yamanaka K, Kamura T, et al.Identification of the von Hippel-Lindau tumor-suppressor protein as part of an active E3 ubiquitin ligase complex. Proceedings of the National Academy of Sciences. 1999; 96(22): 12436-12441. PMid: 10535940. https://doi.org/10.1073/pnas.96.22.12436

[45] Albadari N, Deng S, Li W. The transcriptional factors HIF-1 and HIF-2 and their novel inhibitors in cancer therapy. Expert Opinion on Drug Discovery. 2019; 14(7): 667-682. PMid: 31070059. https://doi.org/10.1080/17460441.2019.1613370

[46] Epstein AC, Gleadle JM, McNeill LA, et al. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell. 2001; 107(1): 43-54. PMid: 11595184. https://doi.org/10.1016/S0092-8674(01)00507-4

[47] Jeong JW, Bae MK, Ahn MY, et al. Regulation and destabilization of HIF-1α by ARD1-mediated acetylation. Cell. 2002; 111(5): 709-720. PMid: 12464182. https://doi.org/10.1016/S0092-8674(02)01085-1

[48] Maxwell PH, Wiesener MS, Chang GW, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999; 399(6733): 271-275. PMid: 10353251. https://doi.org/10.1038/20459

[49] Block KM, Wang H, Szabó LZ, et al. Direct inhibition of hypoxia- inducible transcription factor complex with designed dimeric epidithiodiketopiperazine. Journal of the American Chemical So- ciety. 2009; 131(50): 18078-18088. PMid: 20000859. https://doi.org/10.1021/ja807601b

[50] Dann III CE, Bruick RK, Deisenhofer J.Structure of factor-inhibiting hypoxia-inducible factor 1:An asparaginyl hydroxylase involved in the hypoxic response pathway. Proceedings of the National Academy of Sciences. 2002; 99(24): 15351-15356. PMid:12432100. https://doi.org/10.1073/pnas.202614999

[51] McNeill LA, Hewitson KS, Claridge TD, et al. Hypoxia-inducible factor asparaginyl hydroxylase (FIH-1) catalyses hydroxylation at the β-carbon of asparagine-803. Biochemical Journal. 2002; 367(3): 571-575. PMid: 12215170. https://doi.org/10.1042/bj20021162

[52] Catrina SB, Zheng X. Hypoxia and hypoxia-inducible factors in dia- betes and its complications. Diabetologia. 2021; 64: 709-716. PMid: 33496820. https://doi.org/10.1007/s00125-021-05380-z

[53] Li L, Qu Y, Mao M, et al. The involvement of phosphoinositid 3- kinase/Akt pathway in the activation of hypoxia-inducible factor-1α in the developing rat brain after hypoxia-ischemia. Brain Research. 2008; 1197: 152-158. PMid: 18241842. https://doi.org/10.1016/j.brainres.2007.12.059

[54] Fruman DA, Meyers RE, Cantley LC. Phosphoinositide kinases. An- nual Review of Biochemistry. 1998; 67(1): 481-507. PMid: 9759495. https://doi.org/10.1146/annurev.biochem.67.1.481

[55] Fruman DA, Chiu H, Hopkins BD, et al. The PI3K pathway in human disease. Cell. 2017; 170(4): 605-635. PMid: 28802037. https://doi.org/10.1016/j.cell.2017.07.029

[56] Vara JÁF, Casado E, de Castro J, et al. PI3K/Akt signalling pathway and cancer. Cancer Treatment Reviews. 2004; 30(2): 193-204. PMid: 15023437. https://doi.org/10.1016/j.ctrv.2003.07.007

[57] Pawson T, Nash P. Protein-protein interactions define specificity in signal transduction. Genes & Development. 2000; 14(9): 1027-1047. https://doi.org/10.1101/gad.14.9.1027

[58] Kearney AL, Norris DM, Ghomlaghi M, et al. Akt phosphorylates in- sulin receptor substrate to limit PI3K-mediated PIP 3 synthesis. Elife. 2021; 10: e66942. PMid: 34253290. https://doi.org/10.7554/eLife.66942

[59] Zhang F, Ding T, Yu L, et al. Dexmedetomidine protects against oxygen-glucose deprivation-induced injury through the I2 imida- zoline receptor-PI3K/AKT pathway in rat C6 glioma cells. Jour- nal of Pharmacy and Pharmacology. 2012; 64(1): 120-127. PMid: 22150679. https://doi.org/10.1111/j.2042-7158.2011.01382.x

[60] van den Beucken T, Koritzinsky M, Wouters BG. Translational con- trol of gene expression during hypoxia. Cancer Biology & Therapy. 2006; 5(7): 749-755. PMid: 16861930. https://doi.org/10.4161/cbt.5.7.2972

[61] Hudson CC, Liu M, Chiang GG, et al. Regulation of hypoxia- inducible factor 1α expression and function by the mammalian target of rapamycin. Molecular and Cellular Biology. 2002; 22(20): 7004-7014. PMid: 12242281. https://doi.org/10.1128/MCB.22.20.7004-7014.2002

[62] Conciatori F, Bazzichetto C, Falcone I, et al. Role of mTOR sig- naling in tumor microenvironment: an overview. International Jour- nal of Molecular Sciences. 2018; 19(8): 2453. PMid: 30126252. https://doi.org/10.3390/ijms19082453

[63] Zhong H, Chiles K, Feldser D, et al. Modulation of hypoxia- inducible factor 1α expression by the epidermal growth fac- tor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in hu- man prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Research. 2000; 60(6): 1541-1545.

[64] Xiao Y, Peng H, Hong C, et al. PDGF promotes the warburg ef- fect in pulmonary arterial smooth muscle cells via activation of the PI3K/AKT/mTOR/HIF-1α signaling pathway. Cellular Physi- ology and Biochemistry. 2017; 42(4): 1603-1613. PMid: 28738389. https://doi.org/10.1159/000479401

[65] El-Tanani M, Nsairat H, Aljabali AA, et al. Role of mammalian tar- get of rapamycin (mTOR) signalling in oncogenesis. Life Sciences. 2023; 121662. PMid: 37028545. https://doi.org/10.1016/j.lfs.2023.121662

[66] Ciuffreda L, Falcone I, Incani UC, et al. PTEN expression and func- tion in adult cancer stem cells and prospects for therapeutic target- ing. Advances in Biological Regulation. 2014; 56: 66-80. PMid: 25088603. https://doi.org/10.1016/j.jbior.2014.07.002

[67] Lv X, Li J, Zhang C, et al. The role of hypoxia-inducible factors in tumor angiogenesis and cell metabolism. Genes & Diseases. 2017; 4(1): 19-24. PMid: 30258904. https://doi.org/10.1016/j.gendis.2016.11.003

[68] Maynard M, Ohh M. The role of hypoxia-inducible factors in cancer. Cellular and Molecular Life Sciences. 2007; 64: 2170-2180. PMid: 17514355. https://doi.org/10.1007/s00018-007-7082-2

[69] Junttila MR, Li SP, Westermarck J. Phosphatase-mediated crosstalk between MAPK signaling pathways in the regulation of cell sur- vival. The FASEB Journal. 2008; 22(4): 954-965. PMid: 18039929. https://doi.org/10.1096/fj.06-7859rev

[70] Santarpia L, Lippman SM, El-Naggar AK. Targeting the MAPK- RAS-RAF signaling pathway in cancer therapy. Expert Opinion on Therapeutic Targets. 2012; 16(1): 103-119. PMid: 22239440. https://doi.org/10.1517/14728222.2011.645805

[71] Raoul C, Estévez AG, Nishimune H, et al. Motoneuron death trig- gered by a specific pathway downstream of Fas: potentiation by ALS-linked SOD 1 mutations. Neuron. 2002; 35(6): 1067-1083. PMid: 12354397. https://doi.org/10.1016/S0896-6273(02)00905-4

[72] Albert-Gascó H, Ros-Bernal F, Castillo-Gómez E, et al. MAP/ERK signaling in developing cognitive and emotional function and its ef- fect on pathological and neurodegenerative processes. International Journal of Molecular Sciences. 2020; 21(12): 4471. PMid: 32586047. https://doi.org/10.3390/ijms21124471

[73] Semenza GL.Signal transduction to hypoxia-inducible factor 1. Bio- chemical pharmacology. 2002; 64(5-6): 993-998. PMid: 12213597. https://doi.org/10.1016/S0006-2952(02)01168-1

[74] You Z, Liu SP, Du J, et al. Advancements in MAPK signaling path- ways and MAPK-targeted therapies for ameloblastoma: a review. Journal of Oral Pathology & Medicine. 2019; 48(3): 201-205. PMid: 30489659. https://doi.org/10.1111/jop.12807

[75] Chung E, Kondo M. Role of Ras/Raf/MEK/ERK signaling in phys- iological hematopoiesis and leukemia development. Immunologic Research. 2011; 49: 248-268. PMid: 21170740. https://doi.org/10.1007/s12026-010-8187-5

[76] Wang D, Buchanan FG, Wang H, et al. Prostaglandin E 2 enhances in- testinal adenoma growth via activation of the Ras-mitogen-activated protein kinase cascade. Cancer Research. 2005; 65(5): 1822-1829. PMid: 15753380. https://doi.org/10.1158/0008-5472.CAN-04-3671

[77] Sang N, Stiehl DP, Bohensky J, et al. MAPK signaling up-regulates the activity of hypoxia-inducible factors by its effects on p300. Jour- nal of Biological Chemistry. 2003; 278(16): 14013-14019. PMid: 12588875. https://doi.org/10.1074/jbc.M209702200

[78] Moy JK, Khoutorsky A, Asiedu MN, et al. The MNK-eIF4E signal- ing axis contributes to injury-induced nociceptive plasticity and the development of chronic pain. Journal of Neuroscience. 2017; 37(31): 7481-7499. PMid: 28674170. https://doi.org/10.1523/JNEUROSCI.0220-17.2017

[79] Ichise T, Yoshida N, Ichise H. CBP/p 300 antagonises EGFR-Ras-Erk signalling and suppresses increased Ras-Erk signalling-induced tu- mour formation in mice. The Journal of Pathology. 2019; 249(1): 39-51. PMid: 30953353. https://doi.org/10.1002/path.5279

[80] Baeriswyl V, Christofori G.The angiogenic switch in carcinogenesis. Seminars in Cancer Biology. Elsevier; 2019.

[81] Türkog˘lu SA, Poyrazli F, Babacan D, et al. Hipoksi ve Kanser. Jour- nal of Advanced Research in Natural and Applied Sciences. 2021; 7(3): 450-463. https://doi.org/10.28979/jarnas.930938

[82] Hickey MM, Simon MC. Regulation of angiogenesis by hypoxia and hypoxia-inducible factors. Current Topics in Developmental Biology. 2006; 76: 217-257. PMid: 17118268. https://doi.org/10.1016/S0070-2153(06)76007-0

[83] Prager GW, Poettler M, Unseld M, et al. Angiogenesis in cancer: Anti-VEGF escape mechanisms. Translational Lung Cancer Research. 2012; 1(1): 14.

[84] Zimna A and Kurpisz M. Hypoxia-inducible factor-1 in physiolog- ical and pathophysiological angiogenesis: applications and thera- pies. BioMed Research International. 2015; 2015(1): 549412. PMid: 26146622. https://doi.org/10.1155/2015/549412

[85] Gerri C, Marín-Juez R, Marass M, et al. Hif-1α regulates macrophage-endothelial interactions during blood vessel develop- ment in zebrafish. Nature Communications. 2017; 8(1): 15492. PMid: 28524872. https://doi.org/10.1038/ncomms15492

[86] Razban V, Lotfi AS, Soleimani M, et al. HIF-1α overexpression in- duces angiogenesis in mesenchymal stem cells. BioResearch. 2012; 1(4): 174-183. PMid: 23514846. https://doi.org/10.1089/biores.2012.9905

[87] Guillemin K, Krasnow MA. The hypoxic response: huffing and HIF- ing. Cell. 1997; 89(1): 9-12. PMid: 9094708. https://doi.org/10.1016/S0092-8674(00)80176-2

[88] Semenza GL. Expression of hypoxia-inducible factor 1: mechanisms and consequences. Biochemical Pharmacology. 2000; 59(1): 47-53. PMid: 10605934. https://doi.org/10.1016/S0006-2952(99)00292-0

[89] Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Molecular and Cellular Biology. 1992; 12(12): 5447-5454. PMid: 1448077. https://doi.org/10.1128/mcb.12.12.5447-5454.1992

[90] Cavallaro U, Christofori G. Molecular mechanisms of tumor angio- genesis and tumor progression. Journal of Neuro-oncology. 2000; 50: 63-70. PMid: 11245282. https://doi.org/10.1023/A:1006414621286

[91] Neufeld G, Kessler O, Vadasz Z, et al. The contribution of proangio- genic factors to the progression of malignant disease: role of vascu- lar endothelial growth factor and its receptors. Surgical Oncology Clinics of North America. 2001; 10(2): 339-356. PMid: 11382591. https://doi.org/10.1016/S1055-3207(18)30069-3

[92] Kaelin Jr WG. The von Hippel-Lindau tumor suppressor protein and clear cell renal carcinoma. Clinical Cancer Research. 2007; 13(2): 680s-684s. PMid: 17255293. https://doi.org/10.1158/1078-0432.CCR-06-1865

[93] Kaelin Jr WG. Molecular basis of the VHL hereditary cancer syndrome. Nature Reviews Cancer. 2002; 2(9): 673-682. PMid: 12209156. https://doi.org/10.1038/nrc885

[94] Gingras AC, Raught B, Sonenberg N. Regulation of translation initia- tion by FRAP/mTOR. Genes & Development. 2001; 15(7): 807-826. PMid: 11297505. https://doi.org/10.1101/gad.887201

[95] Fukuda R, Hirota K, Fan F, et al. Insulin-like growth factor 1 induces hypoxia-inducible factor 1-mediated vascular endothelial growth fac- tor expression, which is dependent on MAP kinase and phosphatidyli- nositol 3-kinase signaling in colon cancer cells. Journal of Biolog- ical Chemistry. 2002; 277(41): 38205-38211. PMid: 12149254. https://doi.org/10.1074/jbc.M203781200

[96] Feldser D, Agani F, Iyer NV, et al. Reciprocal positive regulation of hypoxia-inducible factor 1α and insulin-like growth factor 2. Cancer Research. 1999; 59(16): 3915-3918.

[97] Agani F, Semenza GL. Mersalyl is a novel inducer of vascular endothelial growth factor gene expression and hypoxia-inducible factor 1 activity. Molecular Pharmacology. 1998; 54(5): 749-754. https://doi.org/10.1124/mol.54.5.749

[98] Zhang L, Zhou W, Velculescu VE, et al. Gene expression profiles in normal and cancer cells. Science. 1997; 276(5316): 1268-1272. PMid: 9157888. https://doi.org/10.1126/science.276.5316.1268

[99] Laughner E, Taghavi P, Chiles K, et al. HER2 (neu) signaling in- creases the rate of hypoxia-inducible factor 1α (HIF-1α) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Molecular and Cellular Biology. 2001; 21(12): 3995-4004. PMid: 11359907. https://doi.org/10.1128/MCB.21.12.3995-4004.2001

[100] Giri D, Ittmann M. Inactivation of the PTEN tumor suppressor gene is associated with increased angiogenesis in clinically local- ized prostate carcinoma. Human Pathology. 1999; 30(4): 419-424. PMid: 10208463. https://doi.org/10.1016/S0046-8177(99)90117-X

[101] Zundel W, Schindler C, Haas-Kogan D, et al. Loss of PTEN facili- tates HIF-1-mediated gene expression. Genes & Development. 2000; 14(4): 391-396. https://doi.org/10.1101/gad.14.4.391

[102] Ravi R, Mookerjee B, Bhujwalla ZM, et al. Regulation of tu- mor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1α. Genes & Development. 2000; 14(1): 34-44. https://doi.org/10.1101/gad.14.1.34

[103] Bae MK, Ahn MY, Jeong JW, et al. Jab 1 interacts directly with HIF- 1α and regulates its stability. Journal of Biological Chemistry. 2002; 277(1): 9-12. PMid: 11707426. https://doi.org/10.1074/jbc.C100442200

[104] Jiang BH, Agani F, Passaniti A, et al. V-SRC induces expression of hypoxia-inducible factor 1 (HIF-1) and transcription of genes encoding vascular endothelial growth factor and enolase 1: involve- ment of HIF-1 in tumor progression. Cancer Research. 1997; 57(23): 5328-5335.

[105] Datta K, Bellacosa A, Chan TO, et al. Akt is a direct target of the phosphatidylinositol 3-kinase: activation by growth factors, v-src and v-Ha-ras, in Sf9 and mammalian cells. Journal of Bio- logical Chemistry. 1996; 271(48): 30835-30839. PMid: 8940066. https://doi.org/10.1074/jbc.271.48.30835

[106] Rashid M, Ramezani M, Molavi O, et al. Targeting hypoxia-inducible factor 1 alpha augments synergistic effects of chemo/immunotherapy via modulating tumor microenvironment in a breast cancer mouse model. BioImpacts. 2024; 15: 30424. PMid: 40256236. https://doi.org/10.34172/bi.30424

[107] Zhang L, Chen C, Duanmu J, et al. Cryptotanshinone inhibits the growth and invasion of colon cancer by suppressing inflammation and tumor angiogenesis through modulating MMP/TIMP system, PI3K/Akt/mTOR signaling and HIF-1α nuclear translocation. Inter- national Immunopharmacology. 2018; 65: 429-437. PMid: 30388517. https://doi.org/10.1016/j.intimp.2018.10.035

[108] Wang D, Liu X, Li M, Ning J. HIF-1α regulates the cell viability in radioiodine-resistant papillary thyroid carcinoma cells induced by hypoxia through PKM2/NF-κB signaling pathway. Molecular Carcinogenesis. 2024; 63(2): 238-252. PMid: 37861358. https://doi.org/10.1002/mc.23648

[109] Rapisarda A, Uranchimeg B, Sordet O, et al. Topoisomerase I- mediated inhibition of hypoxia-inducible factor 1: mechanism and therapeutic implications. Cancer Research. 2004; 64(4): 1475-1482. PMid: 14983893. https://doi.org/10.1158/0008-5472.CAN-03-3139

[110] Rapisarda A, Uranchimeg B, Scudiero DA, et al. Identification of small molecule inhibitors of hypoxia-inducible factor 1 transcrip- tional activation pathway. Cancer Research. 2002; 62(15): 4316-4324.

[111] Greenberger LM, Horak ID, Filpula D, et al. A RNA antagonist of hypoxia-inducible factor-1α, EZN-2968, inhibits tumor cell growth. Molecular Cancer Therapeutics. 2008; 7(11): 3598-3608. PMid: 18974394. https://doi.org/10.1158/1535-7163.MCT-08-0510

[112] Onnis B, Rapisarda A, Melillo G. Development of HIF-1 inhibitors for cancer therapy. Journal of Cellular and Molecular Medicine. 2009; 13(9a): 2780-2786. PMid: 19674190. https://doi.org/10.1111/j.1582-4934.2009.00876.x

[113] Lee K, Zhang H, Qian DZ, et al.Acriflavine inhibits HIF-1 dimer- ization, tumor growth, and vascularization. Proc. Natl. Acad. Sci. USA. 2009; 106(42): 17910-17915. PMid: 19805192. https://doi.org/10.1073/pnas.0909353106

[114] Arslan MA, Kutuk O, Basaga H. Protein kinases as drug targets in cancer. Current Cancer Drug Targets. 2006; 6(7): 623-634. PMid: 17100568. https://doi.org/10.2174/156800906778742479

[115] Wilhelm SM, Carter C, Tang L, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Research. 2004; 64(19): 7099-7109. PMid: 15466206. https://doi.org/10.1158/0008-5472.CAN-04-1443

[116] Adnane L, Trail PA, Taylor I, et al. Sorafenib (BAY 43-9006, Nexavar®), a dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature. Methods in Enzymology. 2006; 407: 597-612. PMid: 16757355. https://doi.org/10.1016/S0076-6879(05)07047-3

[117] Johnson JC, Martinez O, Honko AN, et al. Pyridinyl imidazole inhibitors of p38 MAP kinase impair viral entry and reduce cy- tokine induction by Zaire ebolavirus in human dendritic cells. An- tiviral Research. 2014; 107: 102-109. PMid: 24815087. https://doi.org/10.1016/j.antiviral.2014.04.014

[118] Davies SP, Reddy H, Caivano M, et al. Specificity and mecha- nism of action of some commonly used protein kinase inhibitors. Biochemical Journal. 2000; 351(1): 95-105. PMid: 10998351. https://doi.org/10.1042/bj3510095

[119] Sandau KB, Faus HG, Brüne B. Induction of hypoxia-inducible- factor 1 by nitric oxide is mediated via the PI 3K pathway. Bio- chemical and Biophysical Research Communications. 2000; 278(1): 263-267. PMid: 11071882. https://doi.org/10.1006/bbrc.2000.3789

[120] Treins C, Giorgetti-Peraldi S, Murdaca J, et al. Insulin stimu- lates hypoxia-inducible factor 1 through a phosphatidylinositol 3-kinase/target of rapamycin-dependent signaling pathway. Jour- nal of Biological Chemistry. 2002; 277(31): 27975-27981. PMid: 12032158. https://doi.org/10.1074/jbc.M204152200

[121] Fang J, Cao Z, Chen YC, et al. 9-β-D-Arabinofuranosyl-2- fluoroadenine inhibits expression of vascular endothelial growth fac- tor through hypoxia-inducible factor-1 in human ovarian cancer cells. Molecular Pharmacology. 2004; 66(1): 178-186. PMid: 15213310. https://doi.org/10.1124/mol.66.1.178

[122] Geng L, Donnelly E, McMahon G, et al. Inhibition of vascular en- dothelial growth factor receptor signaling leads to reversal of tumor resistance to radiotherapy. Cancer Research. 2001; 61(6): 2413-2419.

[123] Schuuring J, Bussink J, Bernsen HJ, et al. Irradiation combined with SU5416: microvascular changes and growth delay in a human xenograft glioblastoma tumor line. International Journal of Radiation Oncology, Biology, Physics. 2005; 61(2): 529-534. PMid: 15667976. https://doi.org/10.1016/j.ijrobp.2004.09.063

[124] Zhong XS, Zheng JZ, Reed E, et al. SU5416 inhibited VEGF and HIF-1α expression through the PI3K/AKT/p70S6K1 signaling path- way. Biochemical and Biophysical Research Communications. 2004; 324(2): 471-480. PMid: 15474452. https://doi.org/10.1016/j.bbrc.2004.09.082

[125] Majumder PK, Febbo PG, Bikoff R, et al. mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nature Medicine. 2004; 10(6): 594-601. PMid: 15156201. https://doi.org/10.1038/nm1052

[126] Brugarolas JB, Vazquez F, Reddy A, et al. TSC 2 regulates VEGF through mTOR-dependent and-independent pathways. Cancer Cell. 2003; 4(2): 147-158. PMid: 12957289. https://doi.org/10.1016/S1535-6108(03)00187-9

[127] Del Bufalo D, Ciuffreda L, Trisciuoglio D, et al. Antiangiogenic po- tential of the mammalian target of rapamycin inhibitor temsirolimus. Cancer Research. 2006; 66(11): 5549-5554. PMid: 16740688. https://doi.org/10.1158/0008-5472.CAN-05-2825

[128] Royce M, Bachelot T, Villanueva C, et al. Everolimus plus endocrine therapy for postmenopausal women with Estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: a clinical trial. JAMA Oncology. 2018; 4(7): 977-984. PMid: 29566104. https://doi.org/10.1001/jamaoncol.2018.0060

[129] Bachelot T, Cottu P, Chabaud S, et al. Everolimus added to adju- vant endocrine therapy in patients with high-risk hormone receptor- positive, human epidermal growth factor receptor 2-negative primary breast cancer. Journal of Clinical Oncology. 2022; 40(32): 3699-3708. PMid: 35605174. https://doi.org/10.1200/JCO.21.02179

[130] Zhang H, Qian DZ, Tan YS, et al. Digoxin and other cardiac gly- cosides inhibit HIF-1α synthesis and block tumor growth. Proceed- ings of the National Academy of Sciences. 2008; 105(50): 19579-19586. PMid: 19020076. https://doi.org/10.1073/pnas.0809763105

[131] Kwitkowski VE, Prowell TM, Ibrahim A, et al. FDA approval summary: temsirolimus as treatment for advanced renal cell car- cinoma. The Oncologist. 2010; 15(4): 428-435. PMid: 20332142. https://doi.org/10.1634/theoncologist.2009-0178

[132] Karlsson M, Zhang C, Méar L, et al. A single-cell type transcrip- tomics map of human tissues. Science Advances. 2021; 7(31): eabh2169. PMid: 34321199. https://doi.org/10.1126/sciadv.abh2169

[133] Priego-Hernández VD, Arizmendi-Izazaga A, Soto-Flores DG, et al. Expression of HIF-1α and genes involved in glucose metabolism is in- creased in cervical cancer and HPV-16-positive cell lines. Pathogens. 2022; 12(1): 33. PMid: 36678382. https://doi.org/10.3390/pathogens12010033

[134] Liu L, Yu J, Liu Y, et al. Hypoxia-driven angiogenesis and metabolic reprogramming in vascular tumors. Frontiers in Cell and Devel- opmental Biology. 2025; 13: 1572909. PMid: 40443737. https://doi.org/10.3389/fcell.2025.1572909

[135] Suárez C, Vieito M, Valdivia A, et al. Selective HIF2A inhibitors in the management of clear cell renal cancer and von hippel-lindau- disease-associated tumors. Medical Sciences. 2023; 11(3): 46. PMid: 37489462. https://doi.org/10.3390/medsci11030046

[136] Fallah J, Brave MH, Weinstock C, et al. FDA approval summary: belzutifan for von Hippel-Lindau disease-associated tumors. Clini- cal Cancer Research. 2022; 28(22): 4843-4848. PMid: 35727604. https://doi.org/10.1158/1078-0432.CCR-22-1054

[137] Choueiri TK, Lee JL, Merchan JR, et al. Casdatifan (Cas) monother- apy in patients (pts) with previously treated clear cell renal cell carcinoma (ccRCC): Safety, efficacy and subgroup analysis across multiple doses from ARC-20, a phase 1 open-label study. Ameri- can Society of Clinical Oncology. Renal Cell Cancer. 2025; 441. https://doi.org/10.1200/JCO.2025.43.5_suppl.441

[138] Choueiri TK, Ornstein MC, Barata PC, et al. Combination casdati- fan plus cabozantinib expansion cohort of phase 1 ARC-20 study in previously treated patients with clear cell renal cell carcinoma. Amer- ican Society of Clinical Oncology. Genitourinary Cancer-Kidney and Bladder. 2025; 4506. https://doi.org/10.1200/JCO.2025.43.16_suppl.4506

[139] Datta A, West C, O’Connor JP, et al. Impact of hypoxia on cervical cancer outcomes. International Journal of Gynecologic Cancer. 2021; 31(11): 1459-1470. PMid: 34593564. https://doi.org/10.1136/ijgc-2021-002806

[140] Khairkhah N, Bolhassani A, Najafipour R. Current and future di- rection in treatment of HPV-related cervical disease. Journal of Molecular Medicine. 2022; 100(6): 829-845. PMid: 35478255. https://doi.org/10.1007/s00109-022-02199-y

[141] Milani A, Basirnejad M, Bolhassani A. Heat-shock proteins in di- agnosis and treatment: An overview of different biochemical and immunological functions. Immunotherapy. 2019; 11(3): 215-239. PMid: 30730280. https://doi.org/10.2217/imt-2018-0105

[142] Bolhassani A, Agi E. Heat shock proteins in infection. Clinica Chim- ica Acta. 2019; 498: 90-100. PMid: 31437446. https://doi.org/10.1016/j.cca.2019.08.015

[143] Powis G, Kirkpatrick L. Hypoxia inducible factor-1α as a cancer drug target. Molecular Cancer Therapeutics. 2004; 3(5): 647-654. PMid: 15141023. https://doi.org/10.1158/1535-7163.647.3.5

[144] Huang LE, Arany Z, Livingston DM, et al. Activation of hypoxia- inducible transcription factor depends primarily upon redox-sensitive stabilization of its α subunit. Journal of Biological Chemistry. 1996; 271(50): 32253-32259. PMid: 8943284. https://doi.org/10.1074/jbc.271.50.32253

[145] Wenger RH, Rolfs A, Marti HH, et al. Nucleotide sequence, chromo- somal assignment and mRNA expression of mouse hypoxia-inducible factor-1α. Biochemical and Biophysical Research Communications. 1996; 223(1): 54-59. PMid: 8660378. https://doi.org/10.1006/bbrc.1996.0845

[146] Semenza GL.Regulation of oxygen homeostasis by hypoxia- inducible factor 1. Physiology. 2009; 24(2): 97-106. PMid: 19364912. https://doi.org/10.1152/physiol.00045.2008

[147] Zhang C, Yang C, Feldman MJ, et al. Vorinostat suppresses hy- poxia signaling by modulating nuclear translocation of hypoxia in- ducible factor 1 alpha. Oncotarget. 2017; 8 (34): 56110-56125. PMid: 28915577. https://doi.org/10.18632/oncotarget.18125

[148] Wiener CM, Booth G, Semenza GL.In vivo expression of mRNAs encoding hypoxia-inducible factor 1. Biochemical and Biophysical Research Communications. 1996; 225(2): 485-488. PMid: 8753788. https://doi.org/10.1006/bbrc.1996.1199

[149] Samanta D, Gilkes DM, Chaturvedi P, et al.Hypoxia-inducible factors are required for chemotherapy resistance of breast cancer stem cells. Proceedings of the National Academy of Sciences. 2014; 111(50): E5429-E5438. PMid:25453096. https://doi.org/10.1073/pnas.1421438111

[150] Zhang C, Yang C, Feldman MJ, et al. Vorinostat suppresses hypoxia signaling by modulating nuclear translocation of hypoxia inducible factor 1 alpha. Oncotarget. 2017; 8(34): 56110. PMid: 28915577. https://doi.org/10.18632/oncotarget.18125

[151] Park K, Lee HE, Lee SH, et al. Molecular and functional evalua- tion of a novel HIF inhibitor, benzopyranyl 1, 2, 3-triazole com- pound. Oncotarget. 2017; 8(5): 7801. PMid: 27999195. https://doi.org/10.18632/oncotarget.13955

[152] Clark AJ, Wiley DT, Zuckerman JE, et al.CRLX101 nanoparti- cles localize in human tumors and not in adjacent, nonneoplas- tic tissue after intravenous dosing. Proceedings of the National Academy of Sciences. 2016; 113(14): 3850-3854. PMid: 27001839. https://doi.org/10.1073/pnas.1603018113

[153] Kim KH, Kim D, Park JY, et al. NNC 55-0396, a T-type Ca 2+ channel inhibitor, inhibits angiogenesis via suppression of hypoxia-inducible factor-1α signal transduction. Journal of Molecu- lar Medicine. 2015; 93: 499-509. PMid: 25471482. https://doi.org/10.1007/s00109-014-1235-1

[154] Huang YC, Huang FI, Mehndiratta S, et al. Anticancer activity of MPT0G157, a derivative of indolylbenzenesulfonamide, inhibits tu- mor growth and angiogenesis. Oncotarget. 2015; 6(21): 18590. PMid: 26087180. https://doi.org/10.18632/oncotarget.4068

[155] Kovacs JJ, Murphy PJ, Gaillard S, et al. HDAC 6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Molecular Cell. 2005; 18(5): 601-607. PMid: 15916966. https://doi.org/10.1016/j.molcel.2005.04.021

[156] Jiang BH, Jiang G, Zheng JZ, et al. Phosphatidylinositol 3-kinase signaling controls levels of hypoxia-inducible factor. Cell Growth and Differentiation. 2001; 12(7): 363-369.

[157] Delmas C, End D, Rochaix P, et al. The farnesyltransferase inhibitor R115777 reduces hypoxia and matrix metalloproteinase 2 expression in human glioma xenograft. Clinical Cancer Research. 2003; 9(16): 6062-6068.

[158] Pucciarelli D, Lengger N, Takácˇová M, et al. Hypoxia increases the heterogeneity of melanoma cell populations and affects the response to vemurafenib. Molecular Medicine Reports. 2016; 13(4): 3281-3288. PMid: 26936534. https://doi.org/10.3892/mmr.2016.4888

[159] Sundar R, Hong DS, Kopetz S, et al. Targeting BRAF-mutant col- orectal cancer: progress in combination strategies. Cancer Discovery. 2017; 7(6): 558-560. PMid: 28576843. https://doi.org/10.1158/2159-8290.CD-17-0087

[160] Sullivan RJ, Infante JR, Janku F, et al. First-in-Class ERK1/2 In- hibitor Ulixertinib (BVD-523) in Patients with MAPK Mutant Ad- vanced Solid Tumors: Results of a Phase I Dose-Escalation and Expansion StudyPhase I Trial of Ulixertinib, an Oral ERK 1/2 In- hibitor. Cancer Discovery. 2018; 8(2): 184-195. PMid: 29247021. https://doi.org/10.1158/2159-8290.CD-17-1119

[161] Aguirre AJ, Nowak JA, Camarda ND, et al. Real-time ge- nomic characterization of advanced pancreatic cancer to enable precision medicine. Cancer Discovery. 2018; 8(9): 1096-1111.PMid: 29903880. https://doi.org/10.1158/2159-8290.CD-18-0275