Abstract
Cancer progression is associated with metabolic reprogramming and causes significant intracellular stress; however, the mechanisms that link cellular stress and growth signalling are not fully understood. Here, we identified a mechanism that couples the mitochondrial stress response (MSR) with tumour progression. We demonstrated that the MSR is activated in a significant proportion of human thyroid cancers via the upregulation of heat shock protein D family members and the mitokine, growth differentiation factor 15. Our study also revealed that MSR triggered AKT/S6K signalling by activating mTORC2 via activating transcription factor 4/sestrin 2 activation whilst promoting leucine transporter and nutrient-induced mTORC1 activation. Importantly, we found that an increase in mtDNA played an essential role in MSR-induced mTOR activation and that crosstalk between MYC and MSR potentiated mTOR activation. Together, these findings suggest that the MSR could be a predictive marker for aggressive human thyroid cancer as well as a useful therapeutic target.
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Data availability
The datasets generated during and/or analysed during this study are available from the corresponding author on reasonable request.
References
Ward PS, Thompson CB. Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. Cancer Cell. 2012;21:297–308.
Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324:1029–33.
Zaugg K, Yao Y, Reilly PT, Kannan K, Kiarash R, Mason J, et al. Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress. Genes Dev. 2011;25:1041–51.
Choo AY, Kim SG, Vander Heiden MG, Mahoney SJ, Vu H, Yoon S-O, et al. Glucose addiction of TSC null cells is caused by failed mTORC1-dependent balancing of metabolic demand with supply. Mol Cell. 2010;38:487–99.
Gao P, Tchernyshyov I, Chang T-C, Lee Y-S, Kita K, Ochi T, et al. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature. 2009;458:762.
Wise DR, DeBerardinis RJ, Mancuso A, Sayed N, Zhang X-Y, Pfeiffer HK, et al. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci USA 2008;105:18782–7.
Vyas S, Zaganjor E, Haigis MC. Mitochondria and cancer. Cell. 2016;166:555–66.
Chandel NS. Evolution of mitochondria as signaling organelles. Cell Metab. 2015;22:204–6.
Quirós PM, Mottis A, Auwerx J. Mitonuclear communication in homeostasis and stress. Nat Rev Mol Cell Biol. 2016;17:213.
Matilainen O, Quirós PM, Auwerx J. Mitochondria and epigenetics–crosstalk in homeostasis and stress. Trends Cell Biol. 2017;27:453–63.
O’Malley J, Kumar R, Inigo J, Yadava N, Chandra D. Mitochondrial stress response and cancer. Trends Cancer. 2020;6:688–701.
Durieux J, Wolff S, Dillin A. The cell-non-autonomous nature of electron transport chain-mediated longevity. Cell. 2011;144:79–91.
Yoneda T, Benedetti C, Urano F, Clark SG, Harding HP, Ron D. Compartment-specific perturbation of protein handling activates genes encoding mitochondrial chaperones. J Cell Sci. 2004;117:4055–66.
Nargund AM, Pellegrino MW, Fiorese CJ, Baker BM, Haynes CM. Mitochondrial import efficiency of ATFS-1 regulates mitochondrial UPR activation. Science. 2012;337:587–90.
Houtkooper RH, Mouchiroud L, Ryu D, Moullan N, Katsyuba E, Knott G, et al. Mitonuclear protein imbalance as a conserved longevity mechanism. Nature. 2013;497:451.
D’Amico D, Sorrentino V, Auwerx J. Cytosolic proteostasis networks of the mitochondrial stress response. Trends Biochem Sci. 2017;42:712–25.
Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, Calfon M, et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell. 2003;11:619–33.
Quiros PM, Prado MA, Zamboni N, D’Amico D, Williams RW, Finley D, et al. Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals. J Cell Biol. 2017;216:2027–45.
Tyynismaa H, Carroll CJ, Raimundo N, Ahola-Erkkilä S, Wenz T, Ruhanen H, et al. Mitochondrial myopathy induces a starvation-like response. Hum Mol Genet. 2010;19:3948–58.
Martínez-Reyes I, Sánchez-Aragó M, Cuezva JM. AMPK and GCN2–ATF4 signal the repression of mitochondria in colon cancer cells. Biochem J. 2012;444:249–59.
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.
Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70.
Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005;307:1098–101.
Zhou Q, Liu C, Liu W, Zhang H, Zhang R, Liu J, et al. Rotenone induction of hydrogen peroxide inhibits mTOR-mediated S6K1 and 4E-BP1/eIF4E pathways, leading to neuronal apoptosis. Toxicol Sci. 2015;143:81–96.
Peng M, Ostrovsky J, Kwon YJ, Polyak E, Licata J, Tsukikawa M, et al. Inhibiting cytosolic translation and autophagy improves health in mitochondrial disease. Hum Mol Genet. 2015;24:4829–47.
Johnson SC, Yanos ME, Kayser EB, Quintana A, Sangesland M, Castanza A, et al. mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome. Science. 2013;342:1524–8.
Zheng X, Boyer L, Jin M, Kim Y, Fan W, Bardy C, et al. Alleviation of neuronal energy deficiency by mTOR inhibition as a treatment for mitochondria-related neurodegeneration. Elife. 2016;5:e13378.
Nacarelli T, Azar A, Sell C. Aberrant mTOR activation in senescence and aging: a mitochondrial stress response? Exp Gerontol. 2015;68:66–70.
Steffen KK, Dillin A. A ribosomal perspective on proteostasis and aging. Cell Metab. 2016;23:1004–12.
Ding L, Bailey MH, Porta-Pardo E, Thorsson V, Colaprico A, Bertrand D, et al. Perspective on oncogenic processes at the end of the beginning of cancer genomics. Cell. 2018;173:305–320.e310.
Bailey MH, Tokheim C, Porta-Pardo E, Sengupta S, Bertrand D, Weerasinghe A, et al. Comprehensive characterization of cancer driver genes and mutations. Cell. 2018;173:371–385.e318.
Taylor AM, Shih J, Ha G, Gao GF, Zhang X, Berger AC, et al. Genomic and functional approaches to understanding cancer aneuploidy. Cancer Cell. 2018;33:676–89.e673.
Zhang Y, Kwok-Shing NgP, Kucherlapati M, Chen F, Liu Y, Tsang YH, et al. A Pan-cancer proteogenomic atlas of PI3K/AKT/mTOR pathway alterations. Cancer Cell. 2017;31:820–832.e823.
Liu J, Lichtenberg T, Hoadley KA, Poisson LM, Lazar AJ, Cherniack AD, et al. An Integrated TCGA Pan-cancer clinical data resource to drive high-quality survival outcome analytics. Cell. 2018;173:400–416.e411.
Sanchez-Vega F, Mina M, Armenia J, Chatila WK, Luna A, La KC, et al. Oncogenic signaling pathways in The Cancer Genome Atlas. Cell. 2018;173:321–337.e310.
Peng X, Chen Z, Farshidfar F, Xu X, Lorenzi PL, Wang Y, et al. Molecular characterization and clinical relevance of metabolic expression subtypes in human cancers. Cell Rep. 2018;23:255–269.e254.
Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, et al. Signatures of mutational processes in human cancer. Nature. 2013;500:415–21.
Agrawal N, Akbani R, Aksoy BA, Ally A, Arachchi H, Asa SL, et al. Integrated genomic characterization of papillary thyroid carcinoma. Cell. 2014;159:676–90.
Bao X, Zhang J, Huang G, Yan J, Xu C, Dou Z, et al. The crosstalk between HIFs and mitochondrial dysfunctions in cancer development. Cell Death Dis. 2021;12:215.
Porporato PE, Filigheddu N, Pedro JMB, Kroemer G, Galluzzi L. Mitochondrial metabolism and cancer. Cell Res. 2018;28:265–80.
Ishida S, Andreux P, Poitry-Yamate C, Auwerx J, Hanahan D. Bioavailable copper modulates oxidative phosphorylation and growth of tumors. Proc Natl Acad Sci USA 2013;110:19507–12.
Yi HS, Chang JY, Shong M. The mitochondrial unfolded protein response and mitohormesis: a perspective on metabolic diseases. J Mol Endocrinol. 2018;61:R91–R105.
Moullan N, Mouchiroud L, Wang X, Ryu D, Williams EG, Mottis A, et al. Tetracyclines disturb mitochondrial function across eukaryotic models: a call for caution in biomedical research. Cell Rep. 2015;10:1681–91.
Byun J-K, Choi Y-K, Kim J-H, Jeong JY, Jeon H-J, Kim M-K, et al. A positive feedback loop between sestrin2 and mTORC2 is required for the survival of glutamine-depleted lung cancer cells. Cell Rep. 2017;20:586–99.
Kowalsky AH, Namkoong S, Mettetal E, Park HW, Kazyken D, Fingar DC, et al. The GATOR2-mTORC2 axis mediates Sestrin2-induced AKT Ser/Thr kinase activation. J Biol Chem. 2020;295:1769–80.
Garaeva AA, Kovaleva IE, Chumakov PM, Evstafieva AG. Mitochondrial dysfunction induces SESN2 gene expression through Activating Transcription Factor 4. Cell Cycle. 2016;15:64–71.
Wolfson RL, Chantranupong L, Saxton RA, Shen K, Scaria SM, Cantor JR, et al. Sestrin2 is a leucine sensor for the mTORC1 pathway. Science. 2016;351:43–48.
Saxton RA, Knockenhauer KE, Wolfson RL, Chantranupong L, Pacold ME, Wang T, et al. Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway. Science. 2016;351:53–58.
Ringel MD, Hayre N, Saito J, Saunier B, Schuppert F, Burch H, et al. Overexpression and overactivation of Akt in thyroid carcinoma. Cancer Res. 2001;61:6105–11.
Vasko V, Espinosa AV, Scouten W, He H, Auer H, Liyanarachchi S, et al. Gene expression and functional evidence of epithelial-to-mesenchymal transition in papillary thyroid carcinoma invasion. Proc Natl Acad Sci USA 2007;104:2803–8.
Knippler CM, Saji M, Rajan N, Porter K, La Perle K, Ringel MD. MAPK- and AKT-activated thyroid cancers are sensitive to group I PAK inhibition. Endocr Relat Cancer. 2019;26:699–712.
Xing M. Molecular pathogenesis and mechanisms of thyroid cancer. Nat Rev Cancer. 2013;13:184–99.
Matts RL, Levin DH, London IM. Effect of phosphorylation of the alpha-subunit of eukaryotic initiation factor 2 on the function of reversing factor in the initiation of protein synthesis. Proc Natl Acad Sci USA 1983;80:2559–63.
Zhang J, Gao Z, Yin J, Quon MJ, Ye J. S6K directly phosphorylates IRS-1 on Ser270 to promote insulin resistance in response to TNF-α signaling through IKK2. J Biol Chem. 2008;283:35375–82.
Um SH, Frigerio F, Watanabe M, Picard F, Joaquin M, Sticker M, et al. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature. 2004;431:200–5.
King MP, Attardi G. Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation. Science. 1989;246:500–3.
Yu M, Shi Y, Wei X, Yang Y, Zhou Y, Hao X, et al. Depletion of mitochondrial DNA by ethidium bromide treatment inhibits the proliferation and tumorigenesis of T47D human breast cancer cells. Toxicol Lett. 2007;170:83–93.
Hsu PP, Sabatini DM. Cancer cell metabolism: Warburg and beyond. Cell. 2008;134:703–7.
Lee MH, Lee SE, Kim DW, Ryu MJ, Kim SJ, Kim SJ, et al. Mitochondrial localization and regulation of BRAFV600E in thyroid cancer: a clinically used RAF inhibitor is unable to block the mitochondrial activities of BRAFV600E. J Clin Endocrinol Metab. 2011;96:E19–30.
Warburg O. On the origin of cancer cells. Science. 1956;123:309–14.
Warburg O. On respiratory impairment in cancer cells. Science. 1956;124:269–70.
Mathupala SP, Ko YH, Pedersen PL. The pivotal roles of mitochondria in cancer: Warburg and beyond and encouraging prospects for effective therapies. Biochim Biophys Acta. 2010;1797:1225–30.
Budanov AV, Shoshani T, Faerman A, Zelin E, Kamer I, Kalinski H, et al. Identification of a novel stress-responsive gene Hi95 involved in regulation of cell viability. Oncogene. 2002;21:6017.
Park H-W, Park H, Ro S-H, Jang I, Semple IA, Kim DN, et al. Hepatoprotective role of Sestrin2 against chronic ER stress. Nat Commun. 2014;5:4233.
Peng M, Yin N, Li MO. Sestrins function as guanine nucleotide dissociation inhibitors for Rag GTPases to control mTORC1 signaling. Cell. 2014;159:122–33.
Ye J, Palm W, Peng M, King B, Lindsten T, Li MO, et al. GCN2 sustains mTORC1 suppression upon amino acid deprivation by inducing Sestrin2. Genes Dev. 2015;29:2331–6.
Chantranupong L, Wolfson RL, Orozco JM, Saxton RA, Scaria SM, Bar-Peled L, et al. The Sestrins interact with GATOR2 to negatively regulate the amino-acid-sensing pathway upstream of mTORC1. Cell Rep. 2014;9:1–8.
Parmigiani A, Nourbakhsh A, Ding B, Wang W, Kim YC, Akopiants K, et al. Sestrins inhibit mTORC1 kinase activation through the GATOR complex. Cell Rep. 2014;9:1281–91.
Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007;129:1261–74.
Chae YC, Vaira V, Caino MC, Tang H-Y, Seo JH, Kossenkov AV, et al. Mitochondrial Akt regulation of hypoxic tumor reprogramming. Cancer Cell. 2016;30:257–72.
Acknowledgements
Anti-SESN2 polyclonal antibodies and SESN2 plasmids were provided by Prof. Soo Han Bae (Severance Biomedical Science Institute and Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 03722, Seoul, South Korea). We thank Ji Young Kim, Hee Chang Yu, Hoyoung Kim, and Hwa Young Lee for their excellent technical support.
Funding
We received funding from the National Research Foundation of Korea grant, funded by the Korean government NRF-2018R1A2B6004179 and NRF-2021R1H1A2012035 (YSJ); NRF-2020R1A2C1006047 (JL); NRF-2020R1I1A1A01069524 (SP); National Research Foundation of Korea GRL grant NRF-2017K1A1A2013124 (JA); École Polytechnique Fédérale de Lausanne (JA and KS); European Research Council ERC-AdG-787702 (JA); Swiss Cancer Research KFS-4226-08-2017 (KS); and Swiss National Science Foundation, Sinergia CRSII3_160798 (KS).
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Conceptualization: JA, JL, and YSJ; Methodology: WKL, SP, SGL, SJ, GL, DR, KS, and JA; Investigation: WKL, SP, SGL, SJ, GL, and DR; Visualization: WKL, SP, SGL, SJ, and GL; Funding acquisition: KS, JA, JL, and YSJ; Project administration: JL and YSJ; Supervision: KS, JA, JL, and YSJ. Writing – original draft: WKL and SP; Writing – review & editing: WKL, SP, SGL, KS, JA, JL, and YSJ.
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Doolittle, W.K.L., Park, S., Lee, S.G. et al. Non-genomic activation of the AKT-mTOR pathway by the mitochondrial stress response in thyroid cancer. Oncogene 41, 4893–4904 (2022). https://doi.org/10.1038/s41388-022-02484-7
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DOI: https://doi.org/10.1038/s41388-022-02484-7
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