Celecoxib suppresses hepatoma stemness and progression by up-regulating PTEN.

Abstract

Celecoxib, a COX-2 inhibitor and non-steroidal anti-inflammatory drug, can prevent several types of cancer, including hepatocellular carcinoma (HCC). Here we show that celecoxib suppressed the self-renewal and drug-pumping functions in HCC cells. Besides, celecoxib depleted CD44+/CD133+ hepatic cancer stem cells (hCSC). Prostaglandin E2 (PGE2) and CD133 overexpression did not reverse the celecoxib-induced depletion of hCSC. Also, celecoxib inhibited progression of rat Novikoff hepatoma. Moreover, a 60-day celecoxib program increased the survival rate of rats with hepatoma. Histological analysis revealed that celecoxib therapy reduced the abundance of CD44+/CD133+ hCSCs in hepatoma tissues. Besides, the hCSCs depletion was associated with elevated apoptosis and blunted proliferation and angiogenesis in hepatoma. Celecoxib therapy activated peroxisome proliferator-activated receptor γ (PPARγ) and up-regulated PTEN, thereby inhibiting Akt and disrupting hCSC expansion. PTEN gene delivery by adenovirus reduced CD44/CD133 expression in vitro and hepatoma formation in vivo. This study suggests that celecoxib suppresses cancer stemness and progression of HCC via activation of PPARγ/PTEN signaling.

• Authors: Tian-Huei Chu, Hoi-Hung Chan, Hsiao-Mei Kuo, Li-Fen Liu, Tsung-Hui Hu, Cheuk-Kwan Sun, Mei-Lang Kung, Shih-Wei Lin, E-Ming Wang, Yi-Ling Ma, Kwan-Hung Cheng, Kwok Hung Lai, Zhi-Hong Wen, Ping-I Hsu, Ming-Hong Tai
• Journal: Oncotarget (Oncotarget) Vol. 5 Issue 6 Pg. 1475-90 (Mar 30 2014) ISSN: 1949-2553 [Electronic] United States
• PMID: 24721996 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CD44 protein, human
• Cyclooxygenase 2 Inhibitors
• Hyaluronan Receptors
• PPAR gamma
• Pyrazoles
• RNA, Messenger
• Sulfonamides
• Cyclooxygenase 2
• Ptgs2 protein, rat
• Proto-Oncogene Proteins c-akt
• PTEN Phosphohydrolase
• PTEN protein, human
• Celecoxib
• Dinoprostone

Topics

• Animals
• Apoptosis (drug effects)
• Blotting, Western
• Carcinoma, Hepatocellular (drug therapy, metabolism, pathology)
• Celecoxib
• Cell Proliferation (drug effects)
• Cyclooxygenase 2 (chemistry, genetics, metabolism)
• Cyclooxygenase 2 Inhibitors (pharmacology)
• Dinoprostone (metabolism)
• Disease Progression
• Flow Cytometry
• Fluorescent Antibody Technique
• Humans
• Hyaluronan Receptors (metabolism)
• Immunoenzyme Techniques
• Liver Neoplasms (drug therapy, metabolism, pathology)
• Male
• Neoplastic Stem Cells (drug effects, metabolism, pathology)
• PPAR gamma (genetics, metabolism)
• PTEN Phosphohydrolase (genetics, metabolism)
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• Pyrazoles (pharmacology)
• RNA, Messenger (genetics)
• Rats
• Rats, Sprague-Dawley
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction
• Sulfonamides (pharmacology)
• Transcriptional Activation
• Tumor Cells, Cultured
• Up-Regulation