期刊
AUTOPHAGY
卷 17, 期 12, 页码 4401-4422出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2021.1917132
关键词
Autophagic arrest; autophagosome-lysosome fusion; cancer; MCOLN1; zinc influx
类别
资金
- National Natural Science Foundation of China [81971212, 82071225, 81772559]
MCOLN1 is a pharmaceutical target in cancer, and its activation can inhibit oncogenic autophagy and trigger cancer cell death by disrupting autophagic flux, regulating zinc release, and interfering with fusion process. In vivo studies confirm that the MCOLN1 agonist, ML-SA5, significantly suppresses tumor growth and improves survival.
Macroautophagy/autophagy is elevated to ensure the high demand for nutrients for the growth of cancer cells. Here we demonstrated that MCOLN1/TRPML1 is a pharmaceutical target of oncogenic autophagy in cancers such as pancreatic cancer, breast cancer, gastric cancer, malignant melanoma, and glioma. First, we showed that activating MCOLN1, by increasing expression of the channel or using the MCOLN1 agonists, ML-SA5 or MK6-83, arrests autophagic flux by perturbing fusion between autophagosomes and lysosomes. Second, we demonstrated that MCOLN1 regulates autophagy by mediating the release of zinc from the lysosome to the cytosol. Third, we uncovered that zinc influx through MCOLN1 blocks the interaction between STX17 (syntaxin 17) in the autophagosome and VAMP8 in the lysosome and thereby disrupting the fusion process that is determined by the two SNARE proteins. Furthermore, we demonstrated that zinc influx originating from the extracellular fluid arrests autophagy by the same mechanism as lysosomal zinc, confirming the fundamental function of zinc as a participant in membrane trafficking. Last, we revealed that activating MCOLN1 with the agonists, ML-SA5 or MK6-83, triggers cell death of a number of cancer cells by evoking autophagic arrest and subsequent apoptotic response and cell cycle arrest, with little or no effect observed on normal cells. Consistent with the in vitro results, administration of ML-SA5 in Patu 8988 t xenograft mice profoundly suppresses tumor growth and improves survival. These results establish that a lysosomal cation channel, MCOLN1, finely controls oncogenic autophagy in cancer by mediating zinc influx into the cytosol.
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