PMCA inhibition reverses drug resistance in clinically refractory cancer patient-derived models

Background Cancer cells have developed molecular strategies to cope with evolutionary stressors in the dynamic tumor microenvironment. Peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC1 alpha) is a metabolic rheostat that regulates diverse cellular adaptive behaviors, including growth and survival. However, the mechanistic role of PGC1 alpha in regulating cancer cell viability under metabolic and genotoxic stress remains elusive.Methods We investigated the PGC1 alpha-mediated survival mechanisms in metabolic stress (i.e., glucose deprivation-induced metabolic stress condition)-resistant cancer cells. We established glucose deprivation-induced metabolic stress-resistant cells (selected cells) from parental tumor cells and silenced or overexpressed PGC1 alpha in selected and parental tumor cells.Results Several in vitro and in vivo mouse experiments were conducted to elucidate the contribution of PGC1 alpha to cell viability in metabolic stress conditions. Interestingly, in the mouse xenograft model of patient-derived drug-resistant cancer cells, each group treated with an anti-cancer drug alone showed no drastic effects, whereas a group that was co-administered an anti-cancer drug and a specific PMCA inhibitor (caloxin or candidate 13) showed marked tumor shrinkage.Conclusions Our results suggest that PGC1 alpha is a key regulator of anti-apoptosis in metabolic and genotoxic stress-resistant cells, inducing PMCA expression and allowing survival in glucose-deprived conditions. We have discovered a novel therapeutic target candidate that could be employed for the treatment of patients with refractory cancers.

Automated summary

In this study, the role of PGC1 alpha in regulating cancer cell viability under metabolic and genotoxic stress was investigated. The findings suggest that PGC1 alpha is a key regulator of anti-apoptosis in metabolic and genotoxic stress-resistant cells, and it may serve as a potential therapeutic target for refractory cancers.