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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

Authors 

Bo Kyung KimS W NamB S MinHyun Seung BanS PaikK LeeJoo-Young ImYoungjoo LeeJ T ParkSeon-Young KimMirang KimH LeeMi Sun Won

Publisher 

Cancer Research UK

Issue Date 

2018

Citation 

British Journal of Cancer

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

Link 

http://dx.doi.org/10.1038/s41416-018-0289-1

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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