Curcumin targets the TFEB-lysosome pathway for induction of autophagy

// Jianbin Zhang 1, 2, 3, * , Jigang Wang 2, * , Jian Xu 3 , Yuanqiang Lu 4 , Jiukun Jiang 4 , Liming Wang 2 , Han-Ming Shen 2, 5 , Dajing Xia 3 1 Clinical Research Institute, Zhejiang Provincial People’s Hospital, Hangzhou, China 2 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 3 School of Public Health, Zhejiang University, Institute of Immunology, Zhejiang University, Hangzhou, China 4 First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China 5 NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore * These authors have contributed equally to this work Correspondence to: Han-Ming Shen, email: phsshm@nus.edu.sg Dajing Xia, email: dxia@zju.edu.cn Keywords: Curcumin, lysosome, mTOR, TFEB, autophagy Received: July 18, 2016 Accepted: September 16, 2016 Published: September 28, 2016 ABSTRACT Curcumin is a hydrophobic polyphenol derived from the herb Curcumalonga and its wide spectrum of pharmacological activities has been widely studied. It has been reported that Curcumin can induce autophagy through inhibition of the Akt-mTOR pathway. However, the effect of Curcumin on lysosome remains largely elusive. In this study, we first found that Curcumin treatment enhances autophagic flux in both human colon cancer HCT116 cells and mouse embryonic fibroblasts (MEFs). Moreover, Curcumin treatment promotes lysosomal function, evidenced by the increased lysosomal acidification and enzyme activity. Second, Curcumin is capable of suppressing the mammalian target of rapamycin (mTOR). Interestingly, Curcumin fails to inhibit mTOR and to activate lysosomal function in Tsc2 -/- MEFs with constitutive activation of mTOR, indicating that Curcumin-mediated lysosomal activation is achieved via suppression of mTOR. Third, Curcumin treatment activates transcription factor EB (TFEB), a key nuclear transcription factor in control of autophagy and lysosome biogenesis and function, based on the following observations: (i) Curcumin directly binds to TFEB, (ii) Curcumin promotes TFEB nuclear translocation; and (iii) Curcumin increases transcriptional activity of TFEB. Finally, inhibition of autophagy and lysosome leads to more cell death in Curcumin-treated HCT116 cells, suggesting that autophagy and lysosomal activation serves as a cell survival mechanism to protect against Curcumin-mediated cell death. Taken together, data from our study provide a novel insight into the regulatory mechanisms of Curcumin on autophagy and lysosome, which may facilitate the development of Curcumin as a potential cancer therapeutic agent.