Metabolic reprogramming of cancer-associated fibroblasts by IDH3α downregulation.
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.
Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China; Institute of Cancer Stem Cell, Dalian Medical University, 9 South Lvshun Road, Dalian, Liaoning 116044, China.
Daoxiang
D
Zhang
Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
Yongbin
Y
Wang
Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
Zhimin
Z
Shi
Markey Cancer Center, University of Kentucky, College of Medicine, 800 Rose Street, Lexington, KY 40536, USA.
Jingyi
J
Liu
Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
Pan
P
Sun
Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
Xiaodan
X
Hou
Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
Jian
J
Zhang
School of Life Sciences, Fudan University, 220 Handan Road, Shanghai 200433, China.
Shimin
S
Zhao
Markey Cancer Center, University of Kentucky, College of Medicine, 800 Rose Street, Lexington, KY 40536, USA. Electronic address: peter.zhou@uky.edu.
Binhua P
BP
Zhou
Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China. Electronic address: jmei@sjtu.edu.cn.
Jun
J
Mi
D000818:Animals; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D015536:Down-Regulation / Q000187:drug effects; D042967:Electron Transport Complex I / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007521:Isocitrate Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007656:Ketoglutaric Acids / Q000378:metabolism; D060847:Metabolic Engineering; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism; D010085:Oxidative Phosphorylation; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D064828:Prolyl Hydroxylases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007656:Ketoglutaric Acids; C554214:MIRN424 microrna, human; D035683:MicroRNAs; D010982:Platelet-Derived Growth Factor; D034741:RNA, Small Interfering; D053773:Transforming Growth Factor beta1; D007521:Isocitrate Dehydrogenase; D064828:Prolyl Hydroxylases; C571350:NDUFA4L2 protein, mouse; D042967:Electron Transport Complex I; D005947:Glucose