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.
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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.
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.