Document Type

Journal Article

Department/Unit

School of Chinese Medicine; Department of Chemistry

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

6-2015

Source Publication Title

Oncotarget

Volume

27

Issue

6

Start Page

24148

End Page

24162

Publisher

Impact Journals

Peer Reviewed

1

Copyright

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.

Funder

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.

DOI

10.18632/oncotarget.4376

Link to Publisher's Edition

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

ISSN (electronic)

19492553

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JA-5307-28024_suppl.pdf (1082 kB)

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