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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Blotting, Western
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Carcinoma, Hepatocellular / drug therapy*
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Carcinoma, Hepatocellular / metabolism
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Carcinoma, Hepatocellular / pathology
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Celecoxib
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Cell Proliferation / drug effects
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Cyclooxygenase 2 / chemistry
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Cyclooxygenase 2 / genetics
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Cyclooxygenase 2 / metabolism
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Cyclooxygenase 2 Inhibitors / pharmacology*
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Dinoprostone / metabolism
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Disease Progression
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Flow Cytometry
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Fluorescent Antibody Technique
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Humans
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Hyaluronan Receptors / metabolism
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Immunoenzyme Techniques
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Liver Neoplasms / drug therapy*
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Liver Neoplasms / metabolism
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Liver Neoplasms / pathology
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Male
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Neoplastic Stem Cells / drug effects
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Neoplastic Stem Cells / metabolism
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Neoplastic Stem Cells / pathology
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PPAR gamma / genetics
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PPAR gamma / metabolism
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PTEN Phosphohydrolase / genetics
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PTEN Phosphohydrolase / metabolism*
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Pyrazoles / pharmacology*
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RNA, Messenger / genetics
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Rats
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Rats, Sprague-Dawley
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Real-Time Polymerase Chain Reaction
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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Sulfonamides / pharmacology*
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Transcriptional Activation
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Tumor Cells, Cultured
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Up-Regulation
Substances
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CD44 protein, human
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Cyclooxygenase 2 Inhibitors
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Hyaluronan Receptors
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PPAR gamma
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Pyrazoles
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RNA, Messenger
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Sulfonamides
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Cyclooxygenase 2
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Ptgs2 protein, rat
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Proto-Oncogene Proteins c-akt
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PTEN Phosphohydrolase
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PTEN protein, human
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Celecoxib
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Dinoprostone