http://dx.doi.org/10.18632/oncotarget.4376">
 

Document Type

Journal Article

Authors

Guo-Qing Chen, Laboratory of Brain and Gut Research, Center for Clinical Research on Chinese Medicine, School of Chinese Medicine, Hong Kong Baptist University
Cheng-Fang Tang, Department of Chemistry, State Key Laboratory of Environmental and Biological Analysis, Hong Kong Baptist University
Xiao-Ke Shi, Laboratory of Brain and Gut Research, Center for Clinical Research on Chinese Medicine, School of Chinese Medicine, Hong Kong Baptist University
Cheng-Yuan Lin, Laboratory of Brain and Gut Research, Center for Clinical Research on Chinese Medicine, School of Chinese Medicine, Hong Kong Baptist University
Sarwat Fatima, Laboratory of Brain and Gut Research, Center for Clinical Research on Chinese Medicine, School of Chinese Medicine, Hong Kong Baptist University
Xiao-Hua Pan, Shen Zhen People's Hospital
Da-Jian Yang, Chongqing Academy of Chinese Materia Medica
Ge Zhang, Laboratory of Brain and Gut Research, Center for Clinical Research on Chinese Medicine, School of Chinese Medicine, Hong Kong Baptist UniversityFollow
Ai-Ping Lu, Laboratory of Brain and Gut Research, Center for Clinical Research on Chinese Medicine, School of Chinese Medicine, Hong Kong Baptist UniversityFollow
Shu-Hai Lin, Laboratory of Brain and Gut Research, Center for Clinical Research on Chinese Medicine, School of Chinese Medicine, Hong Kong Baptist UniversityFollow
Zhao-Xiang Bian, Laboratory of Brain and Gut Research, Center for Clinical Research on Chinese Medicine, School of Chinese Medicine, Hong Kong Baptist UniversityFollow

Department/Unit

School of Chinese Medicine

Title

Halofuginone inhibits colorectal cancer growth through suppression of Akt/mTORC1 signaling and glucose metabolism

Language

English

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.

Keywords

Akt/mTORC1, Anticancer activity, Colorectal cancer, Glucose metabolism, Halofuginone

Publication Date

2015

Source Publication Title

Oncotarget

Volume

27

Issue

6

Start Page

24148

End Page

24162

Publisher

Impact Journals

ISSN (electronic)

19492553

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