한빛사논문
- 조회678
Ki Cheong Park1 , Jung Min Kim1, Sang Yong Kim1, Seok‑Mo Kim1, Jin Hong Lim1, Min Ki Kim2, Sungsoon Fang2, Yonjung Kim3, Gordon B. Mills4, Sung Hoon Noh1 and Jae‑Ho Cheong1,5,6,7*
1 Department of Surgery, Systems Cancer Biology & Biomarker Research Lab, Yonsei University College of Medicine, Seoul, Republic of Korea
2 Severance Biomedical Science Institute, BK21 PLUS project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
3 EONE-DIAGNOMICS Genome Center, New drug R&D Center, 291 Harmony‑ro, Yeonsu‑gu, Incheon 22014, Republic of Korea
4 Department of Systems Biology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA
5 Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
6 YUMC‑KRIBB Medical Convergence Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
7 Department of Biochemistry & Molecular Biology, Systems Cancer Biology & Biomarker Research Lab, Yonsei University College of Medicine, Seoul, Republic of Korea
*Correspondence: Jae‑Ho Cheong
Abstract
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.
논문정보
- Research article
- 2023년 02월 (BRIC 등록일 2023-02-06)
- 국내(교신)+국외 연구진
- 의약학 > 종양의학
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