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PMCA inhibition reverses drug resistance in clinically refractory cancer patient-derived models
Ki Cheong Park1, Jung Min Kim1, Sang Yong Kim1
1Department of Surgery, Systems Cancer Biology & Biomarker Research Lab, Yonsei University College of Medicine, Seoul, Republic of Korea.
Background:
Cancer cells have developed molecular strategies to cope with evolutionary stressors in the dynamic tumor microenvironment. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) is a metabolic rheostat that regulates diverse cellular adaptive behaviors, including growth and survival. However, the mechanistic role of PGC1α in regulating cancer cell viability under metabolic and genotoxic stress remains elusive.
Methods:
We investigated the PGC1α-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 PGC1α in selected and parental tumor cells.
Results:
Several in vitro and in vivo mouse experiments were conducted to elucidate the contribution of PGC1α 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 PGC1α 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.
Insights
Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) helps cancer cells survive metabolic stress by inducing PMCA expression. Inhibiting PMCA alongside anti-cancer drugs shows promise for treating refractory cancers.
Area of Science:
- Cancer Biology
- Metabolic Regulation
- Molecular Mechanisms
Background:
- Cancer cells adapt to tumor microenvironment stressors.
- PGC1α regulates cell growth and survival.
- PGC1α's role in cancer cell viability under stress is unclear.
Purpose of the Study:
- Investigate PGC1α's role in cancer cell survival during metabolic stress.
- Determine PGC1α-mediated mechanisms of resistance to glucose deprivation.
Main Methods:
- Established glucose deprivation-resistant cancer cells.
- Manipulated PGC1α expression (silencing/overexpression).
- Conducted in vitro and in vivo mouse xenograft experiments.
Main Results:
- PGC1α promotes survival in glucose-deprived conditions.
- Co-administration of anti-cancer drugs and PMCA inhibitors caused significant tumor shrinkage in a mouse model.
- Anti-cancer drugs alone had limited effect.
Conclusions:
- PGC1α is a key regulator of anti-apoptosis in stress-resistant cancer cells.
- PGC1α induces PMCA expression, facilitating survival under glucose deprivation.
- PMCA inhibitors represent a novel therapeutic target for refractory cancers.
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