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

Guo Qing Chen, Cheng Fang Tang, Xiao Ke Shi, Cheng Yuan Lin, Sarwat FATIMA, Xiao Hua Pan, Da Jian Yang, Ge ZHANG, Aiping LYU, Shuhai LIN*, Zhaoxiang BIAN

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

36 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)24148-24162
Number of pages15
JournalOncotarget
Volume6
Issue number27
DOIs
Publication statusPublished - 2015

Scopus Subject Areas

  • Oncology

User-Defined Keywords

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

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