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.
Highlights
More than 1.2 million cases are diagnosed with colorectal cancer (CRC) every year, and more than 600 000 die from the disease worldwide
The effect of HF on cell cycle progression was tested in SW480 and HCT116 cell lines by PI staining, followed by fluorescence-activated cell sorting (FACS) analysis
In the functional examination of this study, we found that HF has high toxicity to CRC cells with the lowest concentration of 5.82 nM as IC50 in HCT116 cells after 48 h-treatment
Summary
More than 1.2 million cases are diagnosed with colorectal cancer (CRC) every year, and more than 600 000 die from the disease worldwide. CRC is responsible for 8% of all cancer deaths [1]. In United States, CRC is the second leading cause of death from cancer among adults [2]. Akt activates an array of downstream factors through phosphorylation and regulates cellular metabolism which is rewired in cancer cells [4]. Mammalian target of rapamycin complex 1 (mTORC1), is led by Akt through phosphorylation at Ser 2448. It has been reported the PI3K/Akt/mTOR signaling components were highly activated in glandular elements of colorectal www.impactjournals.com/oncotarget carcinoma and colorectal adenomas with high-grade intraepithelial neoplasia [5], indicating that inhibitors of PI3K/Akt/mTOR signaling may serve as potential antiCRC agents
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