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.
Highlights
Hepatocellular carcinoma (HCC) accounts for 70–85% of liver cancers and is one of the most common malignancies worldwide [1]
We investigated whether conditioned medium (CM) from Clone-9 cells, which contained a high Prostaglandin E2 (PGE2) content, influenced the generation of hepatic cancer stem cells (hCSC) in N1-S1 cells
These results suggest that PGE2 from hepatic tissues induces differential hCSC distribution in Novikoff hepatoma
Summary
Hepatocellular carcinoma (HCC) accounts for 70–85% of liver cancers and is one of the most common malignancies worldwide [1]. Current HCC therapies include surgery, liver transplantation, chemotherapy, transarterial chemoembolization (TAE), and radiofrequency ablation [2]. An inhibitor of multiple kinases, including vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and Raf kinases, is currently the only target therapy for HCC [3, 4]. It has been reported that COX-2 expression is correlated with angiogenesis, invasion, relapse, chemoresistance, and tumorigenesis in HCC [5]. A significant correlation between COX-2 expression and active inflammation in the adjacent non-cancerous liver is associated with shorter disease-free survival in HCC patients [6]. Prostaglandin E2 (PGE2), the major product of COX-2, stimulates the proliferation, migration, and invasion in hepatoma cells by activating β-catenin and Akt signaling [9]
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