Inhibiting MT2‐TFE3‐dependent autophagy enhances melatonin‐induced apoptosis in tongue squamous cell carcinoma |
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| Authors: | Tengfei Fan Huifeng Pi Min Li Zhenhu Ren Zhijing He Feiya Zhu Li Tian Manyu Tu Jia Xie Mengyu Liu Yuming Li Miduo Tan Gaoming Li Weijia Qing Russel J. Reiter Zhengping Yu Hanjiang Wu Zhou Zhou |
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| Affiliation: | 1. Department of Oral and Maxillofacial Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China;2. Department of Occupational Health, Third Military Medical University, Chongqing, China;3. School of Aerospace Medicine, Fourth Military Medical University, Shaanxi, China;4. Department of Oral Maxillofacial‐Head and Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China;5. Institute of Hepatobiliary Surgery, XinQiao Hospital, Third Military Medical University, Chongqing, China;6. Surgery Department of Galactophore, The Central Hospital of Zhuzhou, Zhuzhou, Hunan, China;7. Department of Health Statistics, Third Military Medical University, Chongqing, China;8. The 517th Hospital of PLA, Xinzhou, Shanxi, China;9. Department of Cellular and Structural Biology, The University of Texas Health Science Center at San Antonio, TX, USA;10. Department of Occupational and Environmental Medicine, School of Public Health, Zhejiang University, Hangzhou, China |
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| Abstract: | ![]()
Autophagy modulation is a potential therapeutic strategy for tongue squamous cell carcinoma (TSCC). Melatonin possesses significant anticarcinogenic activity. However, whether melatonin induces autophagy and its roles in cell death in TSCC are unclear. Herein, we show that melatonin induced significant apoptosis in the TSCC cell line Cal27. Apart from the induction of apoptosis, we demonstrated that melatonin‐induced autophagic flux in Cal27 cells as evidenced by the formation of GFP‐LC3 puncta, and the upregulation of LC3‐II and downregulation of SQSTM1/P62. Moreover, pharmacological or genetic blockage of autophagy enhanced melatonin‐induced apoptosis, indicating a cytoprotective role of autophagy in melatonin‐treated Cal27 cells. Mechanistically, melatonin induced TFE3(Ser321) dephosphorylation, subsequently activated TFE3 nuclear translocation, and increased TFE3 reporter activity, which contributed to the expression of autophagy‐related genes and lysosomal biogenesis. Luzindole, a melatonin membrane receptor blocker, or MT2‐siRNA partially blocked the ability of melatonin to promote mTORC1/TFE3 signaling. Furthermore, we verified in a xenograft mouse model that melatonin with hydroxychloroquine or TFE3‐siRNA exerted a synergistic antitumor effect by inhibiting autophagy. Importantly, TFE3 expression positively correlated with TSCC development and poor prognosis in patients. Collectively, we demonstrated that the melatonin‐induced increase in TFE3‐dependent autophagy is mediated through the melatonin membrane receptor in TSCC. These data also suggest that blocking melatonin membrane receptor‐TFE3‐dependent autophagy to enhance the activity of melatonin warrants further attention as a treatment strategy for TSCC. |
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| Keywords: | apoptosis autophagy melatonin melatonin receptor 1B TFE3 tongue squamous cell carcinoma |
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