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

• Authors: 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
• Journal: British journal of cancer (Br J Cancer) Vol. 119 Issue 11 Pg. 1347-1357 (11 2018) ISSN: 1532-1827 [Electronic] England
• PMID: 30420612 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BCL2 protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• IDF-11774
• Macrolides
• Piperazines
• Proto-Oncogene Proteins c-bcl-2
• bafilomycin A1
• Class I Phosphatidylinositol 3-Kinases
• PIK3CA protein, human
• Vacuolar Proton-Translocating ATPases
• Adamantane

Topics

• Adamantane (analogs & derivatives, pharmacology)
• Animals
• Apoptosis (drug effects)
• Autophagy (drug effects)
• Cell Line, Tumor
• Class I Phosphatidylinositol 3-Kinases (genetics)
• Colorectal Neoplasms (enzymology, 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