School of Chinese Medicine; Department of Chemistry
The Akt/mTORC1 pathway plays a central role in the activation of Warburg effect in cancer. Here, we present for the first time that halofuginone (HF) treatment inhibits colorectal cancer (CRC) growth both in vitro and in vivo through regulation of Akt/mTORC1 signaling pathway. Halofuginone treatment of human CRC cells inhibited cell proliferation, induced the generation of reactive oxygen species and apoptosis. As expected, reduced level of NADPH was also observed, at least in part due to inactivation of glucose-6-phosphate dehydrogenase in pentose phosphate pathway upon HF treatment. Given these findings, we further investigated metabolic regulation of HF through Akt/mTORC1-mediated aerobic glycolysis and found that HF downregulated Akt/mTORC1 signaling pathway. Moreover, metabolomics delineated the slower rates in both glycolytic flux and glucose-derived tricarboxylic acid cycle flux. Meanwhile, both glucose transporter GLUT1 and hexokinase-2 in glycolysis were suppressed in CRC cells upon HF treatment, to support our notion that HF regulates Akt/mTORC1 signaling pathway to dampen glucose uptake and glycolysis in CRC cells. Furthermore, HF retarded tumor growth in nude mice inoculated with HCT116 cells, showing the anticancer activity of HF through metabolic regulation of Akt/mTORC1 in CRC.
Akt/mTORC1, Anticancer activity, Colorectal cancer, Glucose metabolism, Halofuginone
Source Publication Title
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
GQC has been supported by Chongqing Science & Technology Commission (2013CSTC-JBKY-01901), SHL has been supported by the National Natural Science Foundation of China (No. 21377106) and ZXB has been supported by RC-IRMC/11-12/02-SCM.
Link to Publisher's Edition
Chen, Guo-Qing, Cheng-Fang Tang, Xiao-Ke Shi, Cheng-Yuan Lin, Sarwat Fatima, Xiao-Hua Pan, Da-Jian Yang, Ge Zhang, Ai-Ping Lu, Shu-Hai Lin, and Zhao-Xiang Bian. "Halofuginone inhibits colorectal cancer growth through suppression of Akt/mTORC1 signaling and glucose metabolism." Oncotarget 27.6 (2015): 24148-24162.
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