Combined Inhibition of p38MAPK and PIKfyve Synergistically Disrupts Autophagy to Selectively Target Cancer Cells.

ABSTRACT: In nutrient-poor conditions, autophagy buffers metabolic stress and counteracts the effects of chemotherapy and radiation on cancer cells, which depend on autophagy for survival. However, clinical trials targeting autophagy have failed to produce successful anticancer treatments using currently available inhibitors. Recent studies have shown that PIKfyve kinase inhibitors disrupt lysosome function in autophagy and can selectively kill certain cancer cells. Analysis of biochemical changes caused by PIKfyve inhibition revealed that resistant cells contain significantly higher levels of cellular p38MAPK protein and phosphorylation. Expression of the lysosomal protein, lysosomal-associated membrane protein 2, carrying phosphomimetic mutations of the p38MAPK phosphorylation sites prevented all

SUBMITTER: O'Connell CE 

PROVIDER: S-EPMC8178204 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature