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

 Ki Cheong Park  ;  Jung Min Kim  ;  Sang Yong Kim  ;  Seok-Mo Kim  ;  Jin Hong Lim  ;  Min Ki Kim  ;  Sungsoon Fang  ;  Yonjung Kim  ;  Gordon B Mills  ;  Sung Hoon Noh  ;  Jae-Ho Cheong 
 BMC MEDICINE, Vol.21(1) : 38, 2023-02 
Journal Title
Issue Date
Animals ; Drug Resistance ; Humans ; Mice ; Neoplasms* / drug therapy ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / genetics ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism ; Stress, Physiological ; Tumor Microenvironment
Candidate 13 ; Drug-resistant cancer ; Glucose deprivation-induced metabolic stress-resistant cancer ; PGC1α ; PMCA
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.
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1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Seok Mo(김석모) ORCID logo https://orcid.org/0000-0001-8070-0573
Noh, Sung Hoon(노성훈) ORCID logo https://orcid.org/0000-0003-4386-6886
Park, Ki Cheong(박기청) ORCID logo https://orcid.org/0000-0002-3435-3985
Cheong, Jae Ho(정재호) ORCID logo https://orcid.org/0000-0002-1703-1781
Fang, Sungsoon(황성순) ORCID logo https://orcid.org/0000-0003-0201-5567
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