title: Inhibition of oxidative stress-elicited AKT activation facilitates PPARγ agonist-mediated inhibition of stem cell character and tumor growth of liver cancer cells.
abstract: Emerging evidence suggests that tumor-initiating cells (TICs) are the most malignant cell subpopulation in tumors because of their resistance to chemotherapy or radiation treatment. Targeting TICs may be a key innovation for cancer treatment. In this study, we found that PPARγ agonists inhibited the cancer stem cell-like phenotype and attenuated tumor growth of human hepatocellular carcinoma (HCC) cells. Reactive oxygen species (ROS) initiated by NOX2 upregulation were partially responsible for the inhibitory effects mediated by PPARγ agonists. However, PPARγ agonist-mediated ROS production significantly activated AKT, which in turn promoted TIC survival by limiting ROS generation. Inhibition of AKT, by either pharmacological inhibitors or AKT siRNA, significantly enhanced PPARγ agonist-mediated inhibition of cell proliferation and stem cell-like properties in HCC cells. Importantly, in nude mice inoculated with HCC Huh7 cells, we demonstrated a synergistic inhibitory effect of the PPARγ agonist rosiglitazone and the AKT inhibitor triciribine on tumor growth. In conclusion, we observed a negative feedback loop between oxidative stress and AKT hyperactivation in PPARγ agonist-mediated suppressive effects on HCCs. Combinatory application of an AKT inhibitor and a PPARγ agonist may provide a new strategy for inhibition of stem cell-like properties in HCCs and treatment of liver cancer.
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China ; Department of Developmental and Regenerative Biology, College of Life Science and Technology, Jinan University, Guangzhou, China.
authors.forename: Lanlan
authors.initials: L
authors.lastname: Liu
authors.forename: Zhaojuan
authors.initials: Z
authors.lastname: Yang
authors.forename: Yingqian
authors.initials: Y
authors.lastname: Xu
authors.forename: Jingyi
authors.initials: J
authors.lastname: Li
authors.forename: Dongxu
authors.initials: D
authors.lastname: Xu
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Jiabin
authors.initials: J
authors.lastname: Sun
authors.forename: Suhua
authors.initials: S
authors.lastname: Xia
authors.forename: Feiyan
authors.initials: F
authors.lastname: Zou
authors.forename: Yongzhong
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D010641:Phenotype; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012263:Ribonucleosides / Q000494:pharmacology / Q000627:therapeutic use; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C477819:15-deoxyprostaglandin J2; D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D047495:PPAR gamma; D010455:Peptides; D017382:Reactive Oxygen Species; D012263:Ribonucleosides; D045162:Thiazolidinediones; D000077154:Rosiglitazone; C023764:triciribine; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D051057:Proto-Oncogene Proteins c-akt; D015230:Prostaglandin D2
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