Celecoxib suppresses hepatoma stemness and progression by up-regulating PTEN
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Tian-Huei Chu1,*, Hoi-Hung Chan2,3,4,5,*, Hsiao-Mei Kuo6, Li-Fen Liu7, Tsung-Hui Hu8, Cheuk-Kwan Sun9, Mei-Lang Kung10, Shih-Wei Lin11, E-Ming Wang2,3, Yi-Ling Ma2, Kwan-Hung Cheng1, Kwok Hung Lai3,4, Zhi-Hong Wen13, Ping-I Hsu3,4 and Ming-Hong Tai1,2,14
1 Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
2 Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
3 Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
4 School of Medicine, National Yang-Ming University, Taipei, Taiwan
5 College of Pharmacy & Health Care, Tajen University, Pingtung County, Taiwan
6 Mitochondrial Research Unit, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
7 Department of Biological Science and Technology, I-Shou University, Kaohsiung, Taiwan
8 Division of Hepato-Gastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan
9 Department of Medical Education, E-DA Hospital, I-Shou University, Kaohsiung, Taiwan
10 Department of Chemistry, National Sun Yat-sen University, Kaohsiung, Taiwan
11 Institute of Marine Biotechnology, National Sun Yat-sen University, Kaohsiung, Taiwan
12 Department of Medical Education; Digestive Center, E-DA Hospital, Kaohsiung County, Taiwan
13 Department of Marine Biotechnology and Resources, Asia-Pacific Ocean Research Center, National Sun Yat-Sen University, Kaohsiung, Taiwan
14 Center for Neuroscience, National Sun Yat-Sen University, Kaohsiung 804, Taiwan
* These authors contributed equally to this work
Ming-Hong Tai, email:
Keywords: hepatocellular carcinoma, hepatic cancer stem cells, celecoxib, prostaglandin E2, phosphatase and tensin homolog.
Received: September 4, 2013 Accepted: December 28, 2013 Published: December 28, 2013
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.
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