Abstract
Transcription factor EB (TFEB) is a master regulator of autophagy activity and lysosomal biogenesis, but its role in autophagy-mediated cell survival and chemotherapy resistance is not completely understood. In this study, we explored whether TFEB played an important role in autophagy-mediated chemotherapy resistance in human cancer LoVo and HeLa cells in vitro. Treatment of human colon cancer LoVo cells with doxorubicin (0.5 μmol/L) induced autophagy activation and nuclear translocation of TFEB, which resulted from inactivation of the mTOR pathway. In both LoVo and HeLa cells, overexpression of TFEB enhanced doxorubicin-induced autophagy activation and significantly decreased doxorubicin-induced cell death, whereas knockdown of TFEB with small interfering RNA blocked doxorubicin-induced autophagy and significantly enhanced the cytotoxicity of doxorubicin. In LoVo cells, autophagy inhibition by 3-methyladenine (3-MA) or knockdown of autophagy-related gene Atg5 increased cell death in response to doxorubicin, and abolished TFEB overexpression-induced chemotherapy resistance, suggesting that the inhibition of autophagy made cancer cells more sensitive to doxorubicin. The results demonstrate that TFEB-mediated autophagy activation decreases the sensitivity of cancer cells to doxorubicin.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Sui X, Chen R, Wang Z, Huang Z, Kong N, Zhang M, et al. Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment. Cell Death Dis 2013; 4: e838.
Jin S, White E . Tumor suppression by autophagy through the management of metabolic stress. Autophagy 2008; 4: 563–6.
Wang C, Hu Q, Shen HM . Pharmacological inhibitors of autophagy as novel cancer therapeutic agents. Pharmacol Res 2016; 105: 164–75.
Levine B, Kroemer G . Autophagy in the pathogenesis of disease. Cell 2008; 132: 27–42.
Vitale I, Manic G, Dandrea V, De Maria R . Role of autophagy in the maintenance and function of cancer stem cells. Int J Dev Biol 2015; 59: 95–108.
Klionsky DJ . Citing recent declines in the discovery of new ATG genes, some scientists now suggest that the end of autophagy research may be within sight. Autophagy 2014; 10: 715–6.
Wesselborg S, Stork B . Autophagy signal transduction by ATG proteins: from hierarchies to networks. Cell Mol Life Sci 2015; 72: 4721–57.
Qian HR, Yang Y . Functional role of autophagy in gastric cancer. Oncotarget 2016; 7: 17641–51.
Pan ST, Li ZL, He ZX, Qiu JX, Zhou SF . Molecular mechanisms for tumour resistance to chemotherapy. Clin Exp Pharmacol Physiol 2016; 43: 723–37.
Xie JM, Li B, Yu HP, Gao QG, Li W, Wu HR, et al. TIGAR has a dual role in cancer cell survival through regulating apoptosis and autophagy. Cancer Res 2014; 74: 5127–38.
Yu HP, Xie JM, Li B, Sun YH, Gao QG, Ding ZH, et al. TIGAR regulates DNA damage and repair through pentosephosphate pathway and Cdk5-ATM pathway. Sci Rep 2015; 5: 9853.
Sardiello M, Ballabio A . Lysosomal enhancement: a CLEAR answer to cellular degradative needs. Cell Cycle 2009; 8: 4021–2.
Sardiello M, Palmieri M, di Ronza A, Medina DL, Valenza M, Gennarino VA, et al. A gene network regulating lysosomal biogenesis and function. Science 2009; 325: 473–7.
Palmieri M, Impey S, Kang H, di Ronza A, Pelz C, Sardiello M, et al. Characterization of the CLEAR network reveals an integrated control of cellular clearance pathways. Hum Mol Genet 2011; 20: 3852–66.
Settembre C, Zoncu R, Medina DL, Vetrini F, Erdin S, Huynh T, et al. A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. EMBO J 2012; 31: 1095–108.
Perera RM, Stoykova S, Nicolay BN, Ross KN, Fitamant J, Boukhali M, et al. Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism. Nature 2015; 524: 361–5.
Giatromanolaki A, Kalamida D, Sivridis E, Karagounis IV, Gatter KC, Harris AL, et al. Increased expression of transcription factor EB (TFEB) is associated with autophagy, migratory phenotype and poor prognosis in non-small cell lung cancer. Lung Cancer 2015; 90: 98–105.
Zhitomirsky B, Assaraf YG . Lysosomal sequestration of hydrophobic weak base chemotherapeutics triggers lysosomal biogenesis and lysosome-dependent cancer multidrug resistance. Oncotarget 2015; 6: 1143–56.
Pan Y, Gao Y, Chen L, Gao G, Dong H, Yang Y, et al. Targeting autophagy augments in vitro and in vivo antimyeloma activity of DNA-damaging chemotherapy. Clin Cancer Res 2011; 17: 3248–58.
He C, Klionsky DJ . Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 2009; 43: 67–93.
Chen S, Rehman SK, Zhang W, Wen A, Yao L, Zhang J . Autophagy is a therapeutic target in anticancer drug resistance. Biochim Biophys Acta 2010; 1806: 220–9.
Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG . Cancer drug resistance: an evolving paradigm. Nat Rev Cancer 2013; 13: 714–26.
Lozy F, Karantza V . Autophagy and cancer cell metabolism. Semin Cell Dev Biol 2012; 23: 395–401.
Dalby KN, Tekedereli I, Lopez-Berestein G, Ozpolat B . Targeting the prodeath and prosurvival functions of autophagy as novel therapeutic strategies in cancer. Autophagy 2010; 6: 322–9.
Yang S, Wang X, Contino G, Liesa M, Sahin E, Ying H, et al. Pancreatic cancers require autophagy for tumor growth. Genes Dev 2011; 25: 717–29.
Bestebroer J, V'Kovski P, Mauthe M, Reggiori F . Hidden behind autophagy: the unconventional roles of ATG proteins. Traffic 2013; 14: 1029–41.
Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 1999; 402: 672–6.
Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A, et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest 2003; 112: 1809–20.
Yue Z, Jin S, Yang C, Levine AJ, Heintz N . Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci U S A 2003; 100: 15077–82.
Takamura A, Komatsu M, Hara T, Sakamoto A, Kishi C, Waguri S, et al. Autophagy-deficient mice develop multiple liver tumors. Genes Dev 2011; 25: 795–800.
Karantza-Wadsworth V, Patel S, Kravchuk O, Chen G, Mathew R, Jin S, et al. Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. Genes Dev 2007; 21: 1621–35.
Mathew R, Karp CM, Beaudoin B, Vuong N, Chen G, Chen HY, et al. Autophagy suppresses tumorigenesis through elimination of p62. Cell 2009; 137: 1062–75.
Lawrence MS, Stojanov P, Mermel CH, Robinson JT, Garraway LA, Golub TR, et al. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature 2014; 505: 495–501.
Mathew R, Karantza-Wadsworth V, White E . Role of autophagy in cancer. Nat Rev Cancer 2007; 7: 961–7.
White E, Karp C, Strohecker AM, Guo Y, Mathew R . Role of autophagy in suppression of inflammation and cancer. Curr Opin Cell Biol 2010; 22: 212–7.
Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, Chen G, et al. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 2006; 10: 51–64.
Maiuri MC, Zalckvar E, Kimchi A, Kroemer G . Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol 2007; 8: 741–52.
Amaravadi RK, Yu D, Lum JJ, Bui T, Christophorou MA, Evan GI, et al. Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J Clin Invest 2007; 117: 326–36.
Acknowledgements
This work was supported by the Jiangsu Provincial Commission of Health and Family Planning 2014 (No YG201402) and 2015 (No YG201503) as well as by Suzhou Wujiang District Science and Technology Bureau 2013 (No WS201301).
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Fang, Lm., Li, B., Guan, Jj. et al. Transcription factor EB is involved in autophagy-mediated chemoresistance to doxorubicin in human cancer cells. Acta Pharmacol Sin 38, 1305–1316 (2017). https://doi.org/10.1038/aps.2017.25
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/aps.2017.25
Keywords
This article is cited by
-
NSCLC cells sustain phase separation of cytoplasmic membrane-less organelles to protect themselves against cisplatin treatment
Acta Pharmacologica Sinica (2025)
-
Doxorubicin-induced chemoresistance in Duke’s type B colon adenocarcinoma cell line is aggravated in the presence of TGF-β2 through non-apoptotic cell death
Clinical and Translational Oncology (2024)
-
Gemcitabine promotes autophagy and lysosomal function through ERK- and TFEB-dependent mechanisms
Cell Death Discovery (2023)
-
Transcriptional regulation of autophagy and its implications in human disease
Cell Death & Differentiation (2023)
-
Meta analysis of bioactive compounds, miRNA, siRNA and cell death regulators as sensitizers to doxorubicin induced chemoresistance
Apoptosis (2022)
