title: Halofuginone inhibits colorectal cancer growth through suppression of Akt/mTORC1 signaling and glucose metabolism.
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.
authors.affiliation: 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.|Chongqing Academy of Chinese Materia Medica, Chongqing, China.
authors.forename: Guo-Qing
authors.initials: GQ
authors.lastname: Chen
authors.affiliation: Department of Chemistry and State Key Laboratory of Environmental and Biological Analysis, Hong Kong Baptist University, Hong Kong SAR, China.|Instrument and Testing Center, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Cheng-Fang
authors.initials: CF
authors.lastname: Tang
authors.affiliation: 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.
authors.forename: Xiao-Ke
authors.initials: XK
authors.lastname: Shi
authors.affiliation: 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.
authors.forename: Cheng-Yuan
authors.initials: CY
authors.lastname: Lin
authors.affiliation: 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.
authors.forename: Sarwat
authors.initials: S
authors.lastname: Fatima
authors.affiliation: Shen Zhen People's Hospital, Shenzhen, China.
authors.forename: Xiao-Hua
authors.initials: XH
authors.lastname: Pan
authors.affiliation: Chongqing Academy of Chinese Materia Medica, Chongqing, China.
authors.forename: Da-Jian
authors.initials: DJ
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Ge
authors.initials: G
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Ai-Ping
authors.initials: AP
authors.lastname: Lu
authors.affiliation: 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.|Department of Chemistry and State Key Laboratory of Environmental and Biological Analysis, Hong Kong Baptist University, Hong Kong SAR, China.
authors.forename: Shu-Hai
authors.initials: SH
authors.lastname: Lin
authors.affiliation: 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.
authors.forename: Zhao-Xiang
authors.initials: ZX
authors.lastname: Bian
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D005260:Female; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006019:Glycolysis; D045325:HCT116 Cells; D006593:Hexokinase / Q000378:metabolism; D006801:Humans; D020287:In Situ Nick-End Labeling; D008055:Lipids / Q000737:chemistry; D000076222:Mechanistic Target of Rapamycin Complex 1; D008516:Medicine, Chinese Traditional; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D046912:Multiprotein Complexes / Q000378:metabolism*; D010427:Pentose Phosphate Pathway; D010880:Piperidines / Q000737:chemistry*; D011500:Protein Synthesis Inhibitors / Q000737:chemistry; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D052999:Quinazolinones / Q000737:chemistry*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D051272:Glucose Transporter Type 1; D008055:Lipids; D046912:Multiprotein Complexes; D010880:Piperidines; D011500:Protein Synthesis Inhibitors; D052999:Quinazolinones; D017382:Reactive Oxygen Species; C495677:SLC2A1 protein, human; D006593:Hexokinase; C000598049:hexokinase 2, mouse; C494918:AKT1 protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D005947:Glucose; C010176:halofuginone
keywords: Akt/mTORC1; anticancer activity; colorectal cancer; glucose metabolism; halofuginone