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.
Highlights
Hepatocellular carcinoma (HCC) ranks as the fifth most common cancer worldwide
We showed that peroxisome proliferator-activated receptor c (PPARc) agonists (15d-PGJ2 or rosiglitazone) effectively inhibited stem cell-like properties in human liver cancer cells, and that NADPH oxidase-2 (NOX2)induced reactive oxygen species (ROS) generation functioned as a key downstream event
Consistent with previous observations that PPARc agonists usually inhibit the proliferation of tumor cells, we found that treatment with 15d-PGJ2, a natural endogenous ligand of PPARc, significantly inhibited cell proliferation in all examined HCC cell lines (Figure 1A)
Summary
Hepatocellular carcinoma (HCC) ranks as the fifth most common cancer worldwide. HCC has a high rate of chemotherapy-resistance and a high incidence of recurrence and metastasis after surgical treatment, which makes it as the third leading cause of cancer mortality [1,2]. The agonists for the activation of PPARc include endogenous lipophilic ligands, such as 15-deoxyD12,14-prostaglandin J2 (15d-PGJ2) and fatty acids, as well as the synthetic thiazolidinediones (a class of anti-diabetic drugs), including rosiglitazone, troglitazone, ciglitazone, pioglitazone and englitazone [13]. Ligand activation of this transcription factor leads to the expression of target genes to control many essential physiological processes, such as metabolism, cell differentiation, apoptosis, and tissue inflammation [14]. PPARc agonists have been recently implicated in driving ET-743-mediated differentiation of myxoid round cell liposarcoma [15] and the inhibition of TICs in brain cancer [25]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
