TRPML1-induced autophagy inhibition triggers mitochondrial mediated apoptosis.

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.

• Authors: Yucheng Liu, Xinyan Wang, Wucheng Zhu, Zhongheng Sui, Xiangqing Wei, Yang Zhang, Jiansong Qi, Yanhong Xing, Wuyang Wang
• Journal: Cancer letters (Cancer Lett) Vol. 541 Pg. 215752 (08 10 2022) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 35644286 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 Elsevier B.V. All rights reserved.

Chemical References

• MCOLN1 protein, human
• Reactive Oxygen Species
• Transient Receptor Potential Channels
• Tumor Suppressor Protein p53

Topics

• Apoptosis
• Autophagy
• Glioblastoma (drug therapy, genetics, metabolism)
• Humans
• Lysosomes (metabolism)
• Melanoma (metabolism)
• Mitochondria (metabolism)
• Reactive Oxygen Species (metabolism)
• Transient Receptor Potential Channels (metabolism)
• Tumor Suppressor Protein p53 (genetics, metabolism)