Details

Autor(en) / Beteiligte

• Liu, Yucheng
• Wang, Xinyan
• Zhu, Wucheng
• Sui, Zhongheng
• Wei, Xiangqing
• Zhang, Yang
• Qi, Jiansong
• Xing, Yanhong
• Wang, Wuyang

Titel

TRPML1-induced autophagy inhibition triggers mitochondrial mediated apoptosis

Ist Teil von

• Cancer letters, 2022-08, Vol.541, p.215752-215752, Article 215752

Ort / Verlag

Ireland: Elsevier B.V

Erscheinungsjahr

2022

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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. •TRPML1-induced autophagy inhibition results in the blockade of mitophagic flux in human melanoma and glioma cells, thus leading to accumulation of damaged mitochondria and concomitant ROS elevation in these cancer cells.•The elevation in ROS levels causes damage to DNA, which in turn elicits p53 activity in human melanoma and glioma cells. The elicited p53 activity triggers mitochondrial mediated apoptosis in cancer cells.•TRPML1-induced autophagy inhibition greatly suppresses growth of human melanoma and glioma both in vitro and in vivo by triggering apoptosis.