Original Article

Transcription factor EB is involved in autophagymediated chemoresistance to doxorubicin in human cancer cells

Authors: FANG Li-mei, LI Bin, GUAN Jun-jie, XU Hai-dong, SHEN Gen-hai, GAO Quan-gen, QIN Zheng-hong
Corresponding to: FAG Li-mei
DOI: 10.1038/aps.2017.25

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.
Keywords: transcription factor EB (TFEB); LoVo cells; HeLa cells; doxorubicin; autophagy; apoptosis; chemotherapy resistance; 3-methyladenine