TY - JOUR
T1 - Downregulation of PCK2 remodels tricarboxylic acid cycle in tumor-repopulating cells of melanoma
AU - Luo, S.
AU - Li, Y.
AU - Ma, R.
AU - Liu, J.
AU - Xu, P.
AU - Zhang, H.
AU - Tang, K.
AU - Ma, J.
AU - Liu, N.
AU - Zhang, Y.
AU - Sun, Y.
AU - Ji, T.
AU - Liang, X.
AU - Yin, X.
AU - Liu, Y.
AU - Tong, W.
AU - Niu, Y.
AU - Wang, N.
AU - Wang, X.
AU - Huang, B.
N1 - This work was supported by National Basic Research Program of China (2014CB542100), National Natural Science Foundation of China (81472653, 81530080, 81661128007) and CAMS Initiative for Innovative Medicine (2016-I2M-1-007).
PY - 2017/6/22
Y1 - 2017/6/22
N2 - For cancer cells to proliferate, a balance must be built between biomass-forming, glucose-metabolized intermediates and ATP production. How intrinsic glucose carbon flow regulates this balance remains unclear. Here we show that mitochondrial phosphoenolpyruvate carboxykinase (PCK2), the hub molecule linking tricarboxylic acid (TCA) cycle, glycolysis and gluconeogenesis by conversion of mitochondrial oxaloacetate (OAA) to phosphoenolpyruvate, regulates glucose carbon flow direction in stem-like cells that repopulate tumors (tumor-repopulating cells (TRCs)). PCK2 downregulation accelerated biosynthesis and transportation of citrate from mitochondria to the cytosol, leading to cytosolic glucose carbon flow via OAA-malate-pyruvate and acetyl-CoA-fatty acid pathways in TRCs. On the other hand, downregulating PCK2 hindered fumarate carbon flows in TCA cycle, leading to attenuated oxidative phosphorylation. In pathological terms, PCK2 overexpression slowed TRC growth in vitro and impeded tumorigenesis in vivo. Overall, our work unveiled unexpected glucose carbon flows of TRCs in melanoma that have implications for targeting metabolic aspects of melanoma.
AB - For cancer cells to proliferate, a balance must be built between biomass-forming, glucose-metabolized intermediates and ATP production. How intrinsic glucose carbon flow regulates this balance remains unclear. Here we show that mitochondrial phosphoenolpyruvate carboxykinase (PCK2), the hub molecule linking tricarboxylic acid (TCA) cycle, glycolysis and gluconeogenesis by conversion of mitochondrial oxaloacetate (OAA) to phosphoenolpyruvate, regulates glucose carbon flow direction in stem-like cells that repopulate tumors (tumor-repopulating cells (TRCs)). PCK2 downregulation accelerated biosynthesis and transportation of citrate from mitochondria to the cytosol, leading to cytosolic glucose carbon flow via OAA-malate-pyruvate and acetyl-CoA-fatty acid pathways in TRCs. On the other hand, downregulating PCK2 hindered fumarate carbon flows in TCA cycle, leading to attenuated oxidative phosphorylation. In pathological terms, PCK2 overexpression slowed TRC growth in vitro and impeded tumorigenesis in vivo. Overall, our work unveiled unexpected glucose carbon flows of TRCs in melanoma that have implications for targeting metabolic aspects of melanoma.
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U2 - 10.1038/onc.2016.520
DO - 10.1038/onc.2016.520
M3 - Article
C2 - 28166201
AN - SCOPUS:85011690589
SN - 0950-9232
VL - 36
SP - 3609
EP - 3617
JO - Oncogene
JF - Oncogene
IS - 25
ER -