2. Academic Validation
  3. TRPML1-induced autophagy inhibition triggers mitochondrial mediated apoptosis

TRPML1-induced autophagy inhibition triggers mitochondrial mediated apoptosis

  • Cancer Lett. 2022 Aug 10;541:215752. doi: 10.1016/j.canlet.2022.215752.
Yucheng Liu 1,  Xinyan Wang 1,  Wucheng Zhu 1,  Zhongheng Sui 1,  Xiangqing Wei 2,  Yang Zhang 1,  Jiansong Qi 3,  Yanhong Xing 4,  Wuyang Wang 5
Affiliations

Affiliations

  • 1 Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, 209 Tongshan Rd, Xuzhou, Jiangsu, 221004, China.
  • 2 Department of Anesthesiology, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226006, China.
  • 3 Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, 209 Tongshan Rd, Xuzhou, Jiangsu, 221004, China; Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, B3H 4R2, Canada. Electronic address: maggie.qi@dal.ca.
  • 4 Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, 209 Tongshan Rd, Xuzhou, Jiangsu, 221004, China. Electronic address: yanhong646@163.com.
  • 5 Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, 209 Tongshan Rd, Xuzhou, Jiangsu, 221004, China. Electronic address: wuyangwang80@gmail.com.
PMID: 35644286 DOI: 10.1016/j.canlet.2022.215752
Abstract

Previous studies have demonstrated that Autophagy tightly regulates Apoptosis. However, the underlying mechanism whereby Autophagy regulates Apoptosis remains unclear. Here, we discover a "autophagy inhibition-mitochondrial turnover disruption-ROS elevation-DNA damage-p53 transactivation-apoptosis" axis that explicates the process of Autophagy modulating Apoptosis. We found that Autophagy inhibition induced by TRPML1, a cationic channel localized in the lysosome, results in accumulation of damaged mitochondria via blocking the mitophagic flux to lysosomes in human melanoma and glioblastoma cells. The disrupted mitochondria turnover leads to ROS elevation, which in turn causes severe damage to DNA in these Cancer cells. Damage to DNA resulted from TRPML1-mediated Autophagy inhibition subsequently activates p53, which ultimately triggers mitochondrial mediated Apoptosis by modulating pro- and anti-apoptosis proteins in these Cancer cells. As a result, by triggering Apoptosis, TRPML1-induced Autophagy inhibition greatly suppresses growth of human melanoma and glioma both in vitro and in vivo. In summary, our findings define the mechanism underling the regulation of Autophagy inhibition in Apoptosis and represent TRPML1 as a novel target for potentially treating melanoma and glioblastoma in the clinical setting.

Keywords

DNA damage; Glioblastoma; Lysosomes; Melanoma; p53.

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