Research Papers:
Halofuginone inhibits colorectal cancer growth through suppression of Akt/mTORC1 signaling and glucose metabolism
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Abstract
Guo-Qing Chen1,2, Cheng-Fang Tang3,4, Xiao-Ke Shi1, Cheng-Yuan Lin1, Sarwat Fatima1, Xiao-Hua Pan5, Da-Jian Yang2, Ge Zhang1, Ai-Ping Lu1, Shu-Hai Lin1,3 and Zhao-Xiang Bian1
1 Laboratory of Brain and Gut Research, Center for Clinical Research on Chinese Medicine, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
2 Chongqing Academy of Chinese Materia Medica, Chongqing, China
3 Department of Chemistry and State Key Laboratory of Environmental and Biological Analysis, Hong Kong Baptist University, Hong Kong SAR, China
4 Instrument and Testing Center, Sun Yat-Sen University, Guangzhou, China
5 Shen Zhen People’s Hospital, Shenzhen, China
Correspondence to:
Shu-Hai Lin, email:
Zhao-Xiang Bian, email:
Keywords: halofuginone, anticancer activity, colorectal cancer, Akt/mTORC1, glucose metabolism
Received: March 11, 2015 Accepted: May 31, 2015 Published: June 08, 2015
Abstract
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.
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