期刊
AUTOPHAGY
卷 18, 期 8, 页码 1932-1954出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2021.2008752
关键词
Autophagic arrest; metastasis; mitochondria turnover; TP53; ROS; MCOLN1
类别
资金
- National Natural Science Foundation of China (NSFC) [81772559, 82101314, 81971212, 81600967]
- NSF grants of the Jiangsu Province [BK20170262]
- Key University Science Research Project of Jiangsu Province [20KJA310001]
- Jiangsu Specially-Appointed Professor award
- Jiangsu Province Innovative and Entrepreneurial Talent program
- Jiangsu Province Innovative and Entrepreneurial Team program
- Natural Science Foundation of Liaoning Province [2021-MS-161]
The study shows that autophagy inhibition induced by MCOLN1/TRPML1 suppresses cancer metastasis through the ROS-mediated TP53/p53 pathway, by inhibiting cell migration, invasion, and inducing accumulation of damaged mitochondria followed by ROS release. The elevated ROS levels trigger TP53 activity which modulates downstream targets involved in the metastatic cascade, such as MMP members and TWIST, to suppress metastasis.
Compelling evidence has demonstrated that macroautophagy/autophagy plays an important role in regulating multiple steps of metastatic cascades; however, the precise role of autophagy in metastasis remains unclear. This study demonstrates that autophagy inhibition induced by MCOLN1/TRPML1 suppresses cancer metastasis by evoking the ROS-mediated TP53/p53 pathway. First, we found that MCOLN1-mediated autophagy inhibition not only profoundly inhibits both migration and invasion in malignant melanoma and glioma cell lines in vitro, but also suppresses melanoma metastasis in vivo. Second, our study reveals that autophagy inhibition induced by MCOLN1 leads to damaged mitochondria accumulation followed by large quantities of ROS release. Third, we demonstrate that the elevated ROS resulting from autophagy inhibition subsequently triggers TP53 activity, which in turn modulates expression of its downstream targets which are involved in a broad spectrum of the metastatic cascade to suppress metastasis including MMP members and TWIST. In summary, our findings have established a mechanism by which autophagy inhibition suppresses metastasis via the ROS-TP53 signaling pathway. More importantly, our study demonstrates that autophagy inhibition through stimulation of MCOLN1 could evidently be one of the therapeutic potentials for combating cancer metastasis.
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