RRC ID 44633
Author Liu L, Yang Z, Xu Y, Li J, Xu D, Zhang L, Sun J, Xia S, Zou F, Liu Y.
Title Inhibition of oxidative stress-elicited AKT activation facilitates PPARγ agonist-mediated inhibition of stem cell character and tumor growth of liver cancer cells.
Journal PLoS ONE
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.
Volume 8(8)
Pages e73038
Published 2013
DOI 10.1371/journal.pone.0073038
PII PONE-D-13-14368
PMID 24023668
PMC PMC3758331
MeSH AC133 Antigen Animals Antigens, CD / metabolism Antineoplastic Combined Chemotherapy Protocols / pharmacology Antineoplastic Combined Chemotherapy Protocols / therapeutic use Carcinoma, Hepatocellular / drug therapy Carcinoma, Hepatocellular / enzymology Carcinoma, Hepatocellular / pathology Cell Line, Tumor Cell Proliferation / drug effects Enzyme Activation / drug effects Glycoproteins / metabolism Humans Liver Neoplasms / drug therapy Liver Neoplasms / enzymology* Liver Neoplasms / pathology* Male Membrane Glycoproteins / metabolism Mice Mice, Nude NADPH Oxidase 2 NADPH Oxidases / metabolism Neoplastic Stem Cells / drug effects Neoplastic Stem Cells / enzymology* Neoplastic Stem Cells / pathology* Oxidative Stress* / drug effects PPAR gamma / agonists* PPAR gamma / metabolism Peptides / metabolism Phenotype Prostaglandin D2 / analogs & derivatives Prostaglandin D2 / pharmacology Proto-Oncogene Proteins c-akt / antagonists & inhibitors Proto-Oncogene Proteins c-akt / metabolism* Reactive Oxygen Species / metabolism Ribonucleosides / pharmacology Ribonucleosides / therapeutic use Rosiglitazone Thiazolidinediones / pharmacology Thiazolidinediones / therapeutic use
IF 2.776
Times Cited 12
Human and Animal Cells