2. Academic Validation
  3. The PGC1α/NRF1-MPC1 axis suppresses tumor progression and enhances the sensitivity to sorafenib/doxorubicin treatment in hepatocellular carcinoma

The PGC1α/NRF1-MPC1 axis suppresses tumor progression and enhances the sensitivity to sorafenib/doxorubicin treatment in hepatocellular carcinoma

  • Free Radic Biol Med. 2021 Feb 1;163:141-152. doi: 10.1016/j.freeradbiomed.2020.11.035.
Chaoqun Wang 1,  Liqian Dong 1,  Xiaozhuang Li 1,  Yao Li 2,  Bao Zhang 1,  Huibo Wu 1,  Benqiang Shen 1,  Panfei Ma 1,  Zuoyu Li 1,  Yang Xu 1,  Bangliang Chen 1,  Shangha Pan 1,  Yao Fu 3,  Zhongqi Huo 4,  Hongchi Jiang 1,  Yaohua Wu 5,  Yong Ma 6
Affiliations

Affiliations

  • 1 Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
  • 2 Department of Intensive Care Unit, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
  • 3 Department of Ultrasound, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
  • 4 Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, Victoria, Australia.
  • 5 Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China; Department of Thyroid Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China. Electronic address: wuyaohua07@163.com.
  • 6 Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China. Electronic address: mayong@ems.hrbmu.edu.cn.
PMID: 33276082 DOI: 10.1016/j.freeradbiomed.2020.11.035
Abstract

Targeting energy metabolism holds the potential to effectively treat a variety of malignant diseases, and Peroxisome Proliferator-activated Receptor gamma coactivator 1 alpha (PGC1α) is a key regulator of energy metabolism. However, PGC1α's role in Cancer, especially in hepatocellular carcinoma (HCC) remains largely unknown. In the present study, we reported that PGC1α was significantly downregulated in HCC cell lines and specimens. Moreover, reduced expression of PGC1α in tumor cells was correlated with poor prognosis. PGC1α overexpression substantially inhibited cell proliferation and induced Apoptosis in vitro and in vivo. On the contrary, the knockdown of PGC1α produced the opposite effect. The mechanism was at least partially due to the upregulation of mitochondrial pyruvate carrier 1 (MPC1) caused by PGC1α, which promoted mitochondrial biogenesis by binding to nuclear respiratory factor 1 (NRF1). Consequently, the production of cellular Reactive Oxygen Species (ROS) caused by mitochondrial oxidation was elevated above a critical threshold for survival. Furthermore, we found that PGC1α could enhance the antitumor activity of sorafenib and doxorubicin in HCC through ROS accumulation-mediated cell death. These results indicate that PGC1α/NRF1-MPC1 axis is involved in HCC progression and could be a promising target for HCC treatment.

Keywords

Apoptosis; Hepatocellular carcinoma; PGC1α; Progression; ROS.

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