Autophagy and thyroid cancer

Abstract

This review provides the up-to-date physiological, pathophysiological, and carcinogenic roles of autophagy in the thyroid. The data on its physiological roles are mainly obtained with genetically engineered mice, demonstrating the importance of autophagy for the maintenance of cell homeostasis and survival as well as provision of building blocks for sufficient synthesis of proteins such as thyroglobulin. Positive and negative controls of autophagic activity by thyrotropin and thyroid hormone, respectively, are now apparent. In thyroid cancer, there is no published study on the role for autophagy in the initiation/development of thyroid cancer, and there exist many inconsistent data regarding its role in established thyroid cancer behavior. For example, definitive conclusions remain to be elucidated regarding the level of autophagic activity in thyroid cancer cells and the effect of autophagy inducers/inhibitors on cancer cell survival/proliferation. Especially, when autophagy is targeted in novel cancer therapeutics, some studies show its pro-survival, but others its anti-survival or context-dependent, effects on thyroid cancer cells. Further studies are in the future necessary to further elucidate the potential of autophagy as a therapeutic target for thyroid cancer.

Keywords

Thyroid / cancer / autophagy / pro-survival / anti-survival

References

[1] Vigneri R,Vigneri P.The changing epidemiology of thyroid cancer: why is incidence increasing?.Curr Opin Oncol2015;27:1-7

[2] The Cancer Genome Atlas Research NIntegrated genomic characterization of papillary thyroid carcinoma..Cell2014;159:676-90 PMCID:PMC4243044

[3] Ravanan P,Talwar P.Autophagy: the spotlight for cellular stress responses..Life Sci2017;188:53-67

[4] Ravikumar B,Davies JE.Regulation of mammalian autophagy in physiology and pathophysiology..Physiol Rev2010;90:1383-435

[5] Klionsky DJ,Abe A.Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)..Autophagy2016;12:1-222 PMCID:PMC4835977

[6] Seglen PO.3-Methyladenine: specific inhibitor of autophagic/lysosomal protein degradation in isolated rat hepatocytes..Proc Natl Acad Sci U S A1982;79:1889-92 PMCID:PMC346086

[7] Fedorko M.Effect of chloroquine on morphology of cytoplasmic granules in maturing human leukocytes--an ultrastructural study..J Clin Invest1967;46:1932-42 PMCID:PMC292946

[8] Fujita K,Xiao Q.Nrf2-mediated induction of p62 controls Toll-like receptor-4-driven aggresome-like induced structure formation and autophagic degradation..Proc Natl Acad Sci U S A2011;108:1427-32 PMCID:PMC3029726

[9] Nakaso K,Nakano T.Transcriptional activation of p62/A170/ZIP during the formation of the aggregates: possible mechanisms and the role in Lewy body formation in Parkinson’s disease..Brain Res2004;1012:42-51

[10] Trocoli A,Richard E.p62/SQSTM1 upregulation constitutes a survival mechanism that occurs during granulocytic differentiation of acute myeloid leukemia cells..Cell Death Differ2014;21:1852-61 PMCID:PMC4227143

[11] Kurashige T,Shimamura M,Nagayama Y.Hormonal regulation of autophagy in thyroid PCCL3 cells and the thyroids of male mice..J Endocr Soc2020;4:054 PMCID:PMC7347287

[12] Mizushima N.How to interpret LC3 immunoblotting..Autophagy2007;3:542-5

[13] Komatsu M,Ueno T.Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice..J Cell Biol2005;169:425-34 PMCID:PMC2171928

[14] Kuma A,Matsui M.The role of autophagy during the early neonatal starvation period..Nature2004;432:1032-6

[15] Komatsu M,Chiba T.Loss of autophagy in the central nervous system causes neurodegeneration in mice..Nature2006;441:880-4

[16] Hara T,Matsui M.Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice..Nature2006;441:885-9

[17] Nakai A,Takeda T.The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress..Nat Med2007;13:619-24

[18] Ebato C,Arakawa M.Autophagy is important in islet homeostasis and compensatory increase of beta cell mass in response to high-fat diet..Cell Metab2008;8:325-32

[19] Napoletano F,Vandenabeele P,Fanto M.Intersections between regulated cell death and autophagy..Trends Cell Biol2019;29:323-38

[20] Bialik S,Kimchi A.Autophagy-dependent cell death - where, how and why a cell eats itself to death..J Cell Sci2018;131:jcs215152

[21] Kurashige T,Shimamura M.Basal autophagy deficiency causes thyroid follicular epithelial cell death in mice..Endocrinology2019;160:2085-92

[22] Grieco G,Delcorte O.Class III PI3K Vps34 controls thyroid hormone production by regulating thyroglobulin iodination, lysosomal proteolysis, and tissue homeostasis..Thyroid2020;30:133-46 PMCID:PMC6983755

[23] Galluzzi L.Autophagy-independent functions of the autophagy machinery..Cell2019;177:1682-99 PMCID:PMC7173070

[24] Levy JMM,Thorburn A.Targeting autophagy in cancer..Nat Rev Cancer2017;17:528-42 PMCID:PMC5975367

[25] Wei WJ,Luo QY.Targeting autophagy in thyroid cancers..Endocr Relat Cancer2019;26:R181-94

[26] Singh SS,Chia AY,Deng S.Dual role of autophagy in hallmarks of cancer..Oncogene2018;37:1142-58

[27] Qu XP,Bhagat G.Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene..J Clin Invest2003;112:1809-20 PMCID:PMC297002

[28] Yue ZY,Yang CW,Heintz N.Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor..Proc Natl Acad Sci U S A2003;100:15077-82 PMCID:PMC299911

[29] Takamura A,Hara T.Autophagy-deficient mice develop multiple liver tumors..Genes Dev2011;25:795-800 PMCID:PMC3078705

[30] Inami Y,Sakamoto A,Nakada K.Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells..J Cell Biol2011;193:275-84 PMCID:PMC3080263

[31] Mathew R,Beaudoin B.Autophagy suppresses tumorigenesis through elimination of p62..Cell2009;137:1062-75 PMCID:PMC2802318

[32] Liang XH,Jiang HH.Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein..J Virol1998;72:8586-96 PMCID:PMC110269

[33] Liu JL,Kim MS.Beclin1 controls the levels of p53 by regulating the deubiquitination activity of USP10 and USP13..Cell2011;147:223-34 PMCID:PMC3441147

[34] Kimmelman AC.The dynamic nature of autophagy in cancer..Genes Dev2011;25:1999-2010 PMCID:PMC3197199

[35] Rebecca VW.Emerging strategies to effectively target autophagy in cancer..Oncogene2016;35:1-11 PMCID:PMC4838040

[36] Rao S,Perlot T.A dual role for autophagy in a murine model of lung cancer..Nat Commun2014;5:3056

[37] Strohecker AM,Karsli-Uzunbas G.Autophagy sustains mitochondrial glutamine metabolism and growth of BrafV600E-driven lung tumors..Cancer Discov2013;3:1272-85 PMCID:PMC3823822

[38] Karsli-Uzunbas G,Price S.Autophagy is required for glucose homeostasis and lung tumor maintenance..Cancer Discov2014;4:914-27 PMCID:PMC4125614

[39] Rosenfeldt MT,Morton JP.p53 status determines the role of autophagy in pancreatic tumour development..Nature2013;504:296-300

[40] Iacobuzio-Donahue CA.Autophagy, p53, and pancreatic cancer..N Engl J Med2014;370:1352-3

[41] Lock R,Kenific CM.Autophagy facilitates glycolysis during Ras-mediated oncogenic transformation..Mol Biol Cell2011;22:165-78 PMCID:PMC3020913

[42] Bae H.Suppression of autophagy by FIP200 deletion impairs DNA damage repair and increases cell death upon treatments with anticancer agents..Mol Cancer Res2011;9:1232-41 PMCID:PMC3175275

[43] Gillespie DA.Autophagy is critically required for DNA repair by homologous recombination..Mol Cell Oncol2016;3:e1030538 PMCID:PMC4845186

[44] Yu WF,Saji M,Jaini R.Cowden syndrome-associated germline succinate dehydrogenase complex subunit D (SDHD) variants cause PTEN-mediated down-regulation of autophagy in thyroid cancer cells..Hum Mol Genet2017;26:1365-75 PMCID:PMC5390680

[45] Plantinga TS,Huijbers A.Role of genetic variants of autophagy genes in susceptibility for non-medullary thyroid cancer and patients outcome..PLoS One2014;9:e94086 PMCID:PMC3989221

[46] Huijbers A,Joosten LA.The effect of the ATG16L1 Thr300Ala polymorphism on susceptibility and outcome of patients with epithelial cell-derived thyroid carcinoma..Endocr Relat Cancer2012;19:L15-8

[47] Mussazhanova Z,Kurashige T,Nakashima M.Causative role for defective expression of mitochondria-eating protein in accumulation of mitochondria in thyroid oncocytic cell tumors..Cancer Sci2020;111:2814-23 PMCID:PMC7419045

[48] Miyamoto Y,Nakamura Y,Miyamoto T.Possible existence of lysosome-like organella within mitochondria and its role in mitochondrial quality control..PLoS One2011;6:e16054 PMCID:PMC3022026

[49] Bonora E,Bonichon F,Romeo G.Novel germline variants identified in the inner mitochondrial membrane transporter TIMM44 and their role in predisposition to oncocytic thyroid carcinomas..Br J Cancer2006;95:1529-36 PMCID:PMC2360750

[50] Lee J,Lee MH,Park JH.Dysregulation of Parkin-mediated mitophagy in thyroid Hurthle cell tumors..Carcinogenesis2015;36:1407-18

[51] Ganly I,Deraje S,Reznik E.Integrated genomic analysis of Hurthle cell cancer reveals oncogenic drivers, recurrent mitochondrial mutations, and unique chromosomal landscapes..Cancer Cell2018;34:256-70.e5 PMCID:PMC6247912

[52] Zhang N,Wang J.Study of autophagy-related protein light chain 3 (LC3)-II expression levels in thyroid diseases..Biomed Pharmacother2015;69:306-10

[53] Jiang NN,Zhao GN.Knockout of ASAP1 induces autophagy in papillary thyroid carcinoma by inhibiting the mTOR signaling pathway..Pathol Res Pract2020;216:152950

[54] Plantinga TS,Morreau H.Autophagy activity is associated with membranous sodium iodide symporter expression and clinical response to radioiodine therapy in non-medullary thyroid cancer..Autophagy2016;12:1195-205 PMCID:PMC4990989

[55] Kinsey CG,Boespflug AM.Protective autophagy elicited by RAF-->MEK-->ERK inhibition suggests a treatment strategy for RAS-driven cancers..Nat Med2019;25:620-7 PMCID:PMC6452642

[56] Faustino A,Pópulo H.mTOR pathway overactivation in BRAF mutated papillary thyroid carcinoma..J Clin Endocrinol Metab2012;97:E1139-49

[57] Morani F,Pagano L.Autophagy and thyroid carcinogenesis: genetic and epigenetic links..Endocr Relat Cancer2014;21:R13-29

[58] Wang Y,Zhao Y.BRAF-activated long non-coding RNA contributes to cell proliferation and activates autophagy in papillary thyroid carcinoma..Oncol Lett2014;8:1947-52 PMCID:PMC4186573

[59] Corazzari M,Ciccosanti F.Oncogenic BRAF induces chronic ER stress condition resulting in increased basal autophagy and apoptotic resistance of cutaneous melanoma..Cell Death Differ2015;22:946-58 PMCID:PMC4423179

[60] Liu YL,Wilmott JS.Noxa upregulation by oncogenic activation of MEK/ERK through CREB promotes autophagy in human melanoma cells..Oncotarget2014;5:11237-51 PMCID:PMC4294377

[61] Kim HM,Koo JS.Expression of autophagy-related proteins in different types of thyroid cancer..Int J Mol Sci2017;18: PMCID:PMC5372556

[62] Li X,Ma H.Beclin 1 is highly expressed in papillary thyroid carcinoma and correlates with lymph node metastasis..Acta Chir Belg2013;113:175-81

[63] Song HJ,Jiao Q.HIF-1α-mediated TERT activation inducing autophagy through mTOR promotes papillary thyroid carcinoma progression during hypoxia stress..Thyroid2020;

[64] Hu G,Zhan H.Identification of an autophagy-related signature predicting overall survival for papillary thyroid carcinoma..Dose Response2020;18:1559325819899265 PMCID:PMC6958655

[65] Zhu HW.Expression levels of ARHI and Beclin1 in thyroid cancer and their relationship with clinical pathology and prognosis..Oncol Lett2020;19:1241-6 PMCID:PMC6956424

[66] Zhang DX,Li JJ.High iodine effects on the proliferation, apoptosis, and migration of papillary thyroid carcinoma cells as a result of autophagy induced by BRAF kinase..Biomed Pharmacother2019;120:109476

[67] Hong Z,Ying C.Chaperone-mediated autophagy governs progression of papillary thyroid carcinoma via PPARγ-SDF1/CXCR4 signaling..J Clin Endocrinol Metab2020;105:dgaa366

[68] Yi HQ,Ge MH.Inhibition of autophagy enhances the targeted therapeutic effect of sorafenib in thyroid cancer..Oncol Rep2018;39:711-20

[69] Fan D,van Hasselt CA.Estrogen receptor alpha induces prosurvival autophagy in papillary thyroid cancer via stimulating reactive oxygen species and extracellular signal regulated kinases..J Clin Endocrinol Metab2015;100:E561-71

[70] Wang WB,Zhao YN.Targeting autophagy sensitizes BRAF-mutant thyroid cancer to vemurafenib..J Clin Endocrinol Metab2017;102:634-43 PMCID:PMC5413163

[71] Feng HR,Kuang J.Apatinib-induced protective autophagy and apoptosis through the AKT-mTOR pathway in anaplastic thyroid cancer..Cell Death Dis2018;9:1030 PMCID:PMC6177436

[72] Meng XR,Zhao JZ.Apatinib inhibits cell proliferation and induces autophagy in human papillary thyroid carcinoma via the PI3K/Akt/mTOR signaling pathway..Front Oncol2020;10:217 PMCID:PMC7078169

[73] Li XB,Song YM,Liu ZW.The mTOR kinase inhibitor CZ415 inhibits human papillary thyroid carcinoma cell growth..Cell Physiol Biochem2018;46:579-90

[74] Gao P,Dong X.The role of autophagy and Beclin-1 in radiotherapy-induced apoptosis in thyroid carcinoma cells..Int J Clin Exp Pathol2019;12:885-92 PMCID:PMC6945190

[75] Zhang L,Gao YY.Apigenin induces autophagic cell death in human papillary thyroid carcinoma BCPAP cells..Food Funct2015;6:3464-72

[76] Run L,Nong XT,Huang X.Involvement of HMGB1 in vemurafenib resistance in thyroid cancer cells harboring BRAF (V600E) mutation by regulating excessive autophagy..Endocrine2020;

[77] Morgan MJ,Owens CR.Metastatic cells are preferentially vulnerable to lysosomal inhibition..Proc Natl Acad Sci U S A2018;115:E8479-e88 PMCID:PMC6130375

[78] Maycotte P,Cummings CT.Chloroquine sensitizes breast cancer cells to chemotherapy independent of autophagy..Autophagy2012;8:200-12 PMCID:PMC3336076

[79] Lee HO,Hudes GR.Hydroxychloroquine destabilizes phospho-S6 in human renal carcinoma cells..PLoS One2015;10:e0131464 PMCID:PMC4489871

[80] Liu J,Zhang HT.Effects of miR-144 on the sensitivity of human anaplastic thyroid carcinoma cells to cisplatin by autophagy regulation..Cancer Biol Ther2018;19:484-96 PMCID:PMC5927701

[81] Zhang Y,Zhu H.Regulation of autophagy by miR-30d impacts sensitivity of anaplastic thyroid carcinoma to cisplatin..Biochem Pharmacol2014;87:562-70 PMCID:PMC3926201

[82] He Q,Sha S.Adenosine 5’-monophosphate-activated protein kinase-dependent mTOR pathway is involved in flavokawain B-induced autophagy in thyroid cancer cells..Cancer Sci2018;109:2576-89 PMCID:PMC6113436

[83] Li S,Wang T.BAG3 promoted starvation-induced apoptosis of thyroid cancer cells via attenuation of autophagy..J Clin Endocrinol Metab2014;99:E2298-307

[84] Zhao YN,Min I.BRAF V600E-dependent role of autophagy in uveal melanoma..J Cancer Res Clin Oncol2017;143:447-55

[85] Liu KP,Li H.BIRC7 promotes epithelial-mesenchymal transition and metastasis in papillary thyroid carcinoma through restraining autophagy..Am J Cancer Res2020;10:78-94 PMCID:PMC7017743

[86] Shen H,Shi HY.MiR-221/222 promote migration and invasion, and inhibit autophagy and apoptosis by modulating ATG10 in aggressive papillary thyroid carcinoma..3 Biotech2020;10:339 PMCID:PMC7363756

[87] Khan AQ,Hakeem I.Sanguinarine induces apoptosis in papillary thyroid cancer cells via generation of reactive oxygen species..Molecules2020;25:1229 PMCID:PMC7179475

[88] Yu HI,Chen SH.Autophagy modulation in human thyroid cancer cells following aloperine treatment..Int J Mol Sci2019;20: PMCID:PMC6862658

[89] Xiang YF,Zhao M.Allicin activates autophagic cell death to alleviate the malignant development of thyroid cancer..Exp Ther Med2018;15:3537-43 PMCID:PMC5841025

[90] Long HL,Wang HL.Mulberry anthocyanins improves thyroid cancer progression mainly by inducing apoptosis and autophagy cell death..Kaohsiung J Med Sci2018;34:255-62

[91] Qin Y,Zhang H.LncRNA GAS8-AS1 inhibits cell proliferation through ATG5-mediated autophagy in papillary thyroid cancer..Endocrine2018;59:555-64

[92] Lin CI,Abramson MA.Autophagy: a new target for advanced papillary thyroid cancer therapy..Surgery2009;146:1208-14

[93] Lin CI,Donner DB.Autophagy induction with RAD001 enhances chemosensitivity and radiosensitivity through Met inhibition in papillary thyroid cancer..Mol Cancer Res2010;8:1217-26

[94] Yang Z,Wei XY,Min ZJ.The SIRT6-Autophagy-Warburg effect axis in papillary thyroid cancer..Front Oncol2020;10:1265 PMCID:PMC7485319

[95] Xu XH,Ren J.Macrophage migration inhibitory factor deficiency augments doxorubicin-induced cardiomyopathy..J Am Heart Assoc2013;2:e000439-e PMCID:PMC3886760

[96] Kawaguchi T,Kanamori H.Prior starvation mitigates acute doxorubicin cardiotoxicity through restoration of autophagy in affected cardiomyocytes..Cardiovasc Res2012;96:456-65

[97] Li DL,Ding G.Doxorubicin blocks cardiomyocyte autophagic flux by inhibiting Lysosome acidification..Circulation2016;133:1668-87 PMCID:PMC4856587

[98] Jin SM,Sohn SY.Role of autophagy in the resistance to tumour necrosis factor-related apoptosis-inducing ligand-induced apoptosis in papillary and anaplastic thyroid cancer cells..Endocrine2014;45:256-62

[99] Nozima BH,Pereira G.FAM129A regulates autophagy in thyroid carcinomas in an oncogene-dependent manner..Endocr Relat Cancer2019;26:227-38

[100] Arakawa S,Yoshida T.Role of Atg5-dependent cell death in the embryonic development of Bax/Bak double-knockout mice..Cell Death Differ2017;24:1598-608 PMCID:PMC5563990

[101] Fulda S.Cell death by autophagy: emerging molecular mechanisms and implications for cancer therapy..Oncogene2015;34:5105-13

[102] Maycotte P,Barnard R.STAT3-mediated autophagy dependence identifies subtypes of breast cancer where autophagy inhibition can be efficacious..Cancer Res2014;74:2579-90 PMCID:PMC4008672

[103] Levy JM,Griesinger AM.Autophagy inhibition improves chemosensitivity in BRAF(V600E) brain tumors..Cancer Discov2014;4:773-80 PMCID:PMC4090283

[104] Xie X,Price S,Mehnert JM.Atg7 overcomes senescence and promotes growth of BrafV600E-driven melanoma..Cancer Discov2015;5:410-23 PMCID:PMC4390491

[105] Galluzzi L,Aaronson SA.Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018..Cell Death Differ2018;25:486-541 PMCID:PMC5864239

[106] Zeybek ND,Kaymaz FF.Rosuvastatin induces apoptosis in cultured human papillary thyroid cancer cells..J Endocrinol2011;210:105-15

[107] Pontini L.Shedding light on the roles of liver X receptors in cancer by using chemical probes..Br J Pharmacol2020;

[108] Bauriaud-Mallet M,Brillouet S.The cholesterol-derived metabolite dendrogenin A functionally reprograms breast adenocarcinoma and undifferentiated thyroid cancer cells..J Steroid Biochem Mol Biol2019;192:105390

[109] Tesselaar MH,Swarts HG,Boerman OC.Digitalis-like compounds facilitate non-medullary thyroid cancer redifferentiation through intracellular Ca2+, FOS, and autophagy-dependent pathways..Mol Cancer Ther2017;16:169-81

[110] Tesselaar MH,Schuurmans I.Digitalislike compounds restore hNIS expression and iodide uptake capacity in anaplastic thyroid cancer..J Nucl Med2018;59:780-6

[111] Schwertheim S,Jastrow H.New insights into intranuclear inclusions in thyroid carcinoma: association with autophagy and with BRAFV600E mutation..PLoS One2019;14:e0226199 PMCID:PMC6913918

[112] Landa I,Korch C,Smallridge RC.Comprehensive genetic characterization of human thyroid cancer cell lines: a validated panel for preclinical studies..Clin Cancer Res2019;25:3141-51 PMCID:PMC6522280