Metabolic Reprogramming of Cancer-Associated Fibroblasts by IDH3α Downregulation

Authors

Daoxiang Zhang, Shanghai Jiao Tong University School of Medicine, China
Yongbin Wang, Shanghai Jiao Tong University School of Medicine, China
Zhimin Shi, Shanghai Jiao Tong University School of Medicine, China
Jingyi Liu, University of Kentucky
Pan Sun, Shanghai Jiao Tong University School of Medicine, China
Xiaodan Hou, Shanghai Jiao Tong University School of Medicine, China
Jian Zhang, Shanghai Jiao Tong University School of Medicine, China
Shimin Zhao, Fudan University, China
Binhua P. Zhou, University of KentuckyFollow
Jun Mi, Shanghai Jiao Tong University School of Medicine, China

Abstract

Cancer-associated fibroblasts (CAFs) provide critical metabolites for tumor growth and undergo metabolic reprogramming to support glycolysis. However, the molecular mechanisms responsible for this change remain unclear. Here, we report that TGF-β1- or PDGF-induced CAFs switch from oxidative phosphorylation to aerobic glycolysis. We identify downregulation of isocitrate dehydrogenase 3α (IDH3α) as a marker for this switch. Furthermore, miR-424 downregulates IDH3α during CAF formation. Downregulation of IDH3α decreases the effective level of α-ketoglutarate (α-KG) by reducing the ratio of α-KG to fumarate and succinate, resulting in PHD2 inhibition and HIF-1α protein stabilization. The accumulation of HIF-1α, in turn, promotes glycolysis by increasing the uptake of glucose, upregulating expression of glycolytic enzymes under normoxic conditions, and inhibiting oxidative phosphorylation by upregulating NDUFA4L2. CAFs from tumor samples exhibit low levels of IDH3α, and overexpression of IDH3α prevents transformation of fibroblasts into CAFs. Our studies reveal IDH3α to be a critical metabolic switch in CAFs.

Document Type

Article

Publication Date

3-3-2015

Notes/Citation Information

Published in Cell Reports, v. 10, no. 8, p. 1335-1348.

©2015 The Authors

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/).

Digital Object Identifier (DOI)

http://dx.doi.org/10.1016/j.celrep.2015.02.006

Funding Information

This study was supported by grants from the National Program on Key Basic Research Project (973 Program, 2012CB910102 and 2012CB967000), the Shanghai Committee of Science and Technology (11DZ2260200), and the National Science Foundation of China (81372194) to J.M.

Repository Citation

Zhang, Daoxiang; Wang, Yongbin; Shi, Zhimin; Liu, Jingyi; Sun, Pan; Hou, Xiaodan; Zhang, Jian; Zhao, Shimin; Zhou, Binhua P.; and Mi, Jun, "Metabolic Reprogramming of Cancer-Associated Fibroblasts by IDH3α Downregulation" (2015). Markey Cancer Center Faculty Publications. 41.
https://uknowledge.uky.edu/markey_facpub/41