Bcl-2-dependent synthetic lethal interaction of the IDF-11774 with the V0 subunit C of vacuolar ATPase (ATP6V0C) in colorectal cancer
Menée sur une lignée cellulaire de cancer humain du côlon et sur des cellules tumorales reprogrammées après prélèvement sur des patients atteints d'un cancer colorectal, cette étude met en évidence une interaction de "létalité synthétique" entre un nouveau médicament candidat, nommé IDF-11774, et le gène ATP6V0C codant pour la sous-unité C du domaine V0 de l'ATPase lysosomale, puis montre que cette interaction dépend de l'expression de Bcl-2, une protéine impliquée dans la régulation de l'apoptose et la formation d'un autolysosome
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-1
α 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.