Qichao Huang1, Jibin Li1, Jinliang Xing2, Weiwei Li1, Hongwei Li3, Xia Ke3, Jing Zhang4, Tingting Ren4, Yukui Shang3, Hushan Yang5, Jianli Jiang6, Zhinan Chen7. 1. State Key Laboratory of Cancer Biology, Cell Engineering Research Center & Department of Cell Biology, Fourth Military Medical University, Xi'an 710032, China; Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China. 2. State Key Laboratory of Cancer Biology, Cell Engineering Research Center & Department of Cell Biology, Fourth Military Medical University, Xi'an 710032, China; Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China. Electronic address: xingjl@fmmu.edu.cn. 3. State Key Laboratory of Cancer Biology, Cell Engineering Research Center & Department of Cell Biology, Fourth Military Medical University, Xi'an 710032, China. 4. Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China. 5. Division of Population Science, Department of Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA. 6. State Key Laboratory of Cancer Biology, Cell Engineering Research Center & Department of Cell Biology, Fourth Military Medical University, Xi'an 710032, China. Electronic address: jiangjl@fmmu.edu.cn. 7. State Key Laboratory of Cancer Biology, Cell Engineering Research Center & Department of Cell Biology, Fourth Military Medical University, Xi'an 710032, China. Electronic address: zhinanchen@fmmu.edu.cn.
Abstract
BACKGROUND & AIMS: Cancer cells exhibit the reprogrammed metabolism characterized by high level of glycolysis even in the presence of oxygen. Aerobic glycolysis, known as the Warburg effect, supplies cancer cells with the substrates required for biomass generation. To date, several intracellular signaling mediators have been identified in metabolic regulation of cancer cells. However, it remains largely ambiguous how molecules on the cell surface are involved in regulation of cancer metabolism. METHODS: In the current study, we established several HCC cell lines differing in their CD147 (a typical transmembrane glycoprotein) expression status by zinc-finger nuclease and RNAi techniques. Then, we systematically investigated the role of CD147 in the regulation of the Warburg effect in HCC cells and explored the underlying mechanism. RESULTS: We found that CD147 significantly contributed to the reprogramming of glucose metabolism in HCC cells through a p53-dependent way. CD147 facilitated the cell surface expression of MCT1 and lactate export, which led to activation of the PI3K/Akt/MDM2 pathway and thus increased p53 degradation. The gain/loss-of-function studies demonstrated that while CD147 promoted glycolysis, mediated by p53-dependent upregulation of GLUT1 and activation of PFKL, it inhibited mitochondrial biogenesis and functions, mediated by p53-dependent downregulation of PGC1α, TFAM, and p53R2. Additionally, proliferation of HCC cells was suppressed by blocking CD147 and/or MCT1, which resulted in down-regulation of glucose metabolism. CONCLUSIONS: We demonstrate that CD147 is a crucial regulator of glucose metabolism.
BACKGROUND & AIMS:Cancer cells exhibit the reprogrammed metabolism characterized by high level of glycolysis even in the presence of oxygen. Aerobic glycolysis, known as the Warburg effect, supplies cancer cells with the substrates required for biomass generation. To date, several intracellular signaling mediators have been identified in metabolic regulation of cancer cells. However, it remains largely ambiguous how molecules on the cell surface are involved in regulation of cancer metabolism. METHODS: In the current study, we established several HCC cell lines differing in their CD147 (a typical transmembrane glycoprotein) expression status by zinc-finger nuclease and RNAi techniques. Then, we systematically investigated the role of CD147 in the regulation of the Warburg effect in HCC cells and explored the underlying mechanism. RESULTS: We found that CD147 significantly contributed to the reprogramming of glucose metabolism in HCC cells through a p53-dependent way. CD147 facilitated the cell surface expression of MCT1 and lactate export, which led to activation of the PI3K/Akt/MDM2 pathway and thus increased p53 degradation. The gain/loss-of-function studies demonstrated that while CD147 promoted glycolysis, mediated by p53-dependent upregulation of GLUT1 and activation of PFKL, it inhibited mitochondrial biogenesis and functions, mediated by p53-dependent downregulation of PGC1α, TFAM, and p53R2. Additionally, proliferation of HCC cells was suppressed by blocking CD147 and/or MCT1, which resulted in down-regulation of glucose metabolism. CONCLUSIONS: We demonstrate that CD147 is a crucial regulator of glucose metabolism.
Authors: J Li; Q Huang; X Long; X Guo; X Sun; X Jin; Z Li; T Ren; P Yuan; X Huang; H Zhang; J Xing Journal: Oncogene Date: 2017-04-24 Impact factor: 9.867