Inhibition of oxidative stress-elicited AKT activation facilitates PPARγ agonist-mediated inhibition of stem cell character and tumor growth of liver cancer cells

Lanlan Liu; Zhaojuan Yang; Yingqian Xu; Jingyi Li; Dongxu Xu; Li Zhang; Jiabin Sun; Suhua Xia; Feiyan Zou; Yongzhong Liu

doi:10.1371/journal.pone.0073038

Inhibition of oxidative stress-elicited AKT activation facilitates PPARγ agonist-mediated inhibition of stem cell character and tumor growth of liver cancer cells

PLoS One. 2013 Aug 30;8(8):e73038. doi: 10.1371/journal.pone.0073038. eCollection 2013.

Authors

Lanlan Liu¹, Zhaojuan Yang, Yingqian Xu, Jingyi Li, Dongxu Xu, Li Zhang, Jiabin Sun, Suhua Xia, Feiyan Zou, Yongzhong Liu

Affiliation

¹ 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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

15-deoxyprostaglandin J2
AC133 Antigen
Antigens, CD
Glycoproteins
Membrane Glycoproteins
PPAR gamma
Peptides
Reactive Oxygen Species
Ribonucleosides
Thiazolidinediones
Rosiglitazone
triciribine
CYBB protein, human
NADPH Oxidase 2
NADPH Oxidases
Proto-Oncogene Proteins c-akt
Prostaglandin D2

Grants and funding

This work was supported by Chinese National Key Project (2013ZX10002-011). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.