title: Blocking preferential glucose uptake sensitizes liver tumor-initiating cells to glucose restriction and sorafenib treatment.
abstract: Cancer cells display altered metabolic phenotypes characterized by a high level of glycolysis, even under normoxic conditions. Because of a high rate of glycolytic flux and inadequate vascularization, tumor cells often suffer from nutrient deficiency and require metabolic adaptations to address such stresses. Although tumor-initiating cells (T-ICs) have been identified in various malignancies, the cells' metabolic phenotypes remain elusive. In this study, we observed that liver T-ICs preferentially survived under restricted glucose treatment. These cell populations compete successfully for glucose uptake by preferentially expressing glucose transporters (GLUT1 and GLUT3), whereas inhibition of GLUT1 or GLUT3 abolished the survival advantage and suppressed the tumorigenic potential of liver T-ICs. Among signaling pathways related to T-ICs, IL-6/STAT3 was identified to be responsible for the elevation of glucose uptake in liver T-ICs under glucose limitation. Further investigation revealed that IL-6 stimulation upregulated GLUT1 and GLUT3 expressions in CD133+cells, particularly during glucose deprivation. More importantly, inhibition of glucose uptake sensitized liver T-ICs to sorafenib treatment and enhanced the therapeutic efficacy in vivo. Our findings suggest that blocking IL-6/STAT3-mediated preferential glucose uptake might be exploited for novel therapeutic targets during hepatocellular carcinoma (HCC) progression.
authors.affiliation: Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China.
authors.forename: Hui-Lu
authors.initials: HL
authors.lastname: Zhang
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, China.
authors.forename: Ming-Da
authors.initials: MD
authors.lastname: Wang
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhou
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, China.
authors.forename: Chen-Jie
authors.initials: CJ
authors.lastname: Qin
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, China.
authors.forename: Gong-Bo
authors.initials: GB
authors.lastname: Fu
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, China; National Center for Liver Cancer Research, Shanghai 201805, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Tang
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, China.
authors.forename: Han
authors.initials: H
authors.lastname: Wu
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Huang
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, China.
authors.forename: Ling-Hao
authors.initials: LH
authors.lastname: Zhao
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, China.
authors.forename: Min
authors.initials: M
authors.lastname: Zeng
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Liu
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Cao
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, China.
authors.forename: Lin-Na
authors.initials: LN
authors.lastname: Guo
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, China; National Center for Liver Cancer Research, Shanghai 201805, China. Electronic address: hywangk@vip.sina.com.
authors.forename: Hong-Yang
authors.initials: HY
authors.lastname: Wang
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, China; National Center for Liver Cancer Research, Shanghai 201805, China. Electronic address: hexinyw@163.com.
authors.forename: He-Xin
authors.initials: HX
authors.lastname: Yan
authors.affiliation: Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China. Electronic address: jieliu@fudan.edu.cn.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D005947:Glucose / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D000077157:Sorafenib
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib; D005947:Glucose
keywords: GLUT1/3; Glucose uptake; IL-6/STAT3; Nutrition stress; Sorafenib; Tumor-initiating cells