title: Regulation of stem-like cancer cells by glutamine through β-catenin pathway mediated by redox signaling.
abstract: Cancer stem cells (CSCs) are thought to play an important role in tumor recurrence and drug resistance, and present a major challenge in cancer therapy. The tumor microenvironment such as growth factors, nutrients and oxygen affect CSC generation and proliferation by providing the necessary energy sources and growth signals. The side population (SP) analysis has been used to detect the stem-like cancer cell populations based on their high expression of ABCG2 that exports Hoechst-33342 and certain cytotoxic drugs from the cells. The purpose of this research is to investigate the effect of a main nutrient molecule, glutamine, on SP cells and the possible underlying mechanism(s).
  
  
  
  Biochemical assays and flow cytometric analysis were used to evaluate the effect of glutamine on stem-like side population cells in vitro. Molecular analyses including RNAi interfering, qRT-PCR, and immunoblotting were employed to investigate the molecular signaling in response to glutamine deprivation and its influence on tumor formation capacity in vivo.
  
  
  
  We show that glutamine supports the maintenance of the stem cell phenotype by promoting glutathione synthesis and thus maintaining redox balance for SP cells. A deprivation of glutamine in the culture medium significantly reduced the proportion of SP cells. L-asparaginase, an enzyme that catalyzes the hydrolysis of asparagine and glutamine to aspartic acid and glutamate, respectively, mimics the effect of glutamine withdrawal and also diminished the proportion of SP cells. Mechanistically, glutamine deprivation increases intracellular ROS levels, leading to down-regulation of the β-catenin pathway.
  
  
  
  Glutamine plays a significant role in maintaining the stemness of cancer cells by a redox-mediated mechanism mediated by β-catenin. Inhibition of glutamine metabolism or deprivation of glutamine by L-asparaginase may be a new strategy to eliminate CSCs and overcome drug resistance.
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.|Department of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Liao
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
authors.forename: Pan-Pan
authors.initials: PP
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
authors.forename: Guoxin
authors.initials: G
authors.lastname: Hou
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan East Road, Guangzhou, 510006, China.
authors.forename: Jiajia
authors.initials: J
authors.lastname: Shao
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.|Department of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
authors.forename: Kaiyan
authors.initials: K
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
authors.forename: Wenhua
authors.initials: W
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
authors.forename: Shijun
authors.initials: S
authors.lastname: Wen
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
authors.forename: Yumin
authors.initials: Y
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China. phuang@mdanderson.org.|Department of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA. phuang@mdanderson.org.
authors.forename: Peng
authors.initials: P
authors.lastname: Huang
mesh_terms: D000072283:A549 Cells; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000378:metabolism*; D000818:Animals; D001215:Asparaginase / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005973:Glutamine / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D058985:Side-Population Cells / Q000187:drug effects / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects*
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D009363:Neoplasm Proteins; D005973:Glutamine; D001215:Asparaginase; D005978:Glutathione
keywords: Cancer stem cell; Glutamine; L-asparaginase; ROS; Side population; Sox2; β-catenin