ATP Production - Springer Nature

PLK1 inhibition selectively induces apoptosis in ARID1A deficient cells through uncoupling of oxygen consumption from ATP production

However, PLK1 overexpression in cancer does not indicate drug tolerance, and the clinical development of PLK1 inhibitors has been hampered by a lack of a patient selection indicator. Cells deficient for the tumor suppressor ARID1A are extremely sensitive to PLK1 inhibition, according to a high-throughput chemical screen. PLK1 inhibitor sensitivity in ARID1A deficient cells has been found to be dependent on the mitochondrial translation machinery, according to a whole-genome CRISPR screen. PLK1 inhibition in ARID1A KO cells also increases oxygen consumption from ATP manufacture, despite subsequent membrane depolarization and apoptosis. These results, as well as a plan for therapeutic use of PLK1 inhibitors, highlight a new interphase role for PLK1 in maintaining mitochondrial health under metabolic strain. To summarize these results, we introduce a quantitative microscopy assay for determining ARID1A protein loss, which may be a novel patient selection tactic for cancer-related PLK1 inhibitors.

Source link: https://doi.org/10.1038/s41388-022-02219-8

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