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

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Title
Bcl-2-dependent synthetic lethal interaction of the IDF-11774 with the V0 subunit C of vacuolar ATPase (ATP6V0C) in colorectal cancer = 대장암에서의 Bcl-2-의존적인 IDF-11774와 ATP6V0C 합성치사
Author(s)
Bo Kyung Kim; S W Nam; B S Min; Hyun Seung Ban; S Paik; K Lee; Joo-Young Im; Youngjoo Lee; J T Park; Seon-Young KimMirang Kim; H Lee; Mi Sun Won
Bibliographic Citation
British Journal of Cancer, vol. 119, no. 11, pp. 1347-1357
Publication Year
2018
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.
ISSN
0007-0920
Publisher
Springer-Nature Pub Group
DOI
http://dx.doi.org/10.1038/s41416-018-0289-1
Type
Article
Appears in Collections:
Division of Biomedical Research > Personalized Genomic Medicine Research Center > 1. Journal Articles
Division of Biomedical Research > Biotherapeutics Translational Research Center > 1. Journal Articles
Korea Bioinformation Center > 1. Journal Articles
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