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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 
 British Journal of Cancer, Vol.119(11) : 1347-1357, 2018 
Journal Title
 British Journal of Cancer 
Issue Date
Adamantane/analogs & derivatives* ; Adamantane/pharmacology ; Animals ; Apoptosis/drug effects ; Autophagy/drug effects ; Cell Line, Tumor ; Class I Phosphatidylinositol 3-Kinases/genetics ; Colorectal Neoplasms/enzymology* ; Colorectal Neoplasms/pathology ; Female ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Macrolides/pharmacology ; Mice ; Piperazines/pharmacology* ; Proto-Oncogene Proteins c-bcl-2/metabolism* ; Vacuolar Proton-Translocating ATPases/antagonists & inhibitors* ; Xenograft Model Antitumor Assays
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.
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1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Min, Byung Soh(민병소) ORCID logo https://orcid.org/0000-0003-0180-8565
Paik, Soon Myung(백순명) ORCID logo https://orcid.org/0000-0001-9688-6480
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