Bcl-2-dependent synthetic lethal interaction of the IDF-11774 with the V0 subunit C of vacuolar ATPase (ATP6V0C) in colorectal cancer

Bo Kyung Kim, Soon Woo Nam, Byung Soh Min, Hyun Seung Ban, Soonmyung Paik, Kyeong Lee, Joo Young Im, Youngjoo Lee, Joon Tae Park, Seon Young Kim, Mirang Kim, Hongsub Lee, Misun Won

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Background: The IDF-11774, a novel clinical candidate for cancer therapy, targets HSP70 and inhibits mitochondrial respiration, resulting in the activation of AMPK and reduction in HIF-1α accumulation. Methods: To identify genes that have synthetic lethality to IDF-11774, RNA interference screening was conducted, using pooled lentiviruses expressing a short hairpin RNA library. Results: We identified ATP6V0C, encoding the V0 subunit C of lysosomal V-ATPase, knockdown of which induced a synergistic growth-inhibitory effect in HCT116 cells in the presence of IDF-11774. The synthetic lethality of IDF-11774 with ATP6V0C possibly correlates with IDF-11774-mediated autolysosome formation. Notably, the synergistic effect of IDF-11774 and the ATP6V0C inhibitor, bafilomycin A1, depended on the PIK3CA genetic status and Bcl-2 expression, which regulates autolysosome formation and apoptosis. Similarly, in an experiment using conditionally reprogramed cells derived from colorectal cancer patients, synergistic growth inhibition was observed in cells with low Bcl-2 expression. Conclusions: Bcl-2 is a biomarker for the synthetic lethal interaction of IDF-11774 with ATP6V0C, which is clinically applicable for the treatment of cancer patients with IDF-11774 or autophagy-inducing anti-cancer drugs.

Original languageEnglish
Pages (from-to)1347-1357
Number of pages11
JournalBritish Journal of Cancer
Volume119
Issue number11
DOIs
StatePublished - 27 Nov 2018

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