Format

Send to

Choose Destination
Mol Cancer Res. 2017 Sep;15(9):1230-1242. doi: 10.1158/1541-7786.MCR-17-0061. Epub 2017 Jun 5.

PPARδ Reprograms Glutamine Metabolism in Sorafenib-Resistant HCC.

Author information

1
Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
2
Research Institute of Aging and Metabolism, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
3
Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, Republic of Korea.
4
Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Republic of Korea. kpark@knu.ac.kr leei@knu.ac.kr.

Abstract

The tyrosine kinase inhibitor sorafenib is the only therapeutic agent approved for the treatment of advanced hepatocellular carcinoma (HCC), but acquired resistance to sorafenib is high. Here, we report metabolic reprogramming in sorafenib-resistant HCC and identify a regulatory molecule, peroxisome proliferator-activated receptor-δ (PPARδ), as a potential therapeutic target. Sorafenib-resistant HCC cells showed markedly higher glutamine metabolism and reductive glutamine carboxylation, which was accompanied by increased glucose-derived pentose phosphate pathway and glutamine-derived lipid biosynthetic pathways and resistance to oxidative stress. These glutamine-dependent metabolic alterations were attributed to PPARδ, which was upregulated in sorafenib-resistant HCC cells and human HCC tissues. Furthermore, PPARδ contributed to increased proliferative capacity and redox homeostasis in sorafenib-resistant HCC cells. Accordingly, inhibiting PPARδ activity reversed compensatory metabolic reprogramming in sorafenib-resistant HCC cells and sensitized them to sorafenib. Therefore, targeting compensatory metabolic reprogramming of glutamine metabolism in sorafenib-resistant HCC by inhibiting PPARδ constitutes a potential therapeutic strategy for overcoming sorafenib-resistance in HCC.Implications: This study provides novel insight into the mechanism underlying sorafenib resistance and a potential therapeutic strategy targeting PPARδ in advanced hepatocellular carcinoma. Mol Cancer Res; 15(9); 1230-42. ©2017 AACR.

PMID:
28584024
DOI:
10.1158/1541-7786.MCR-17-0061
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center