Celecoxib suppresses hepatoma stemness and progression by up-regulating PTEN.
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.
Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan.
Tian-Huei
TH
Chu
Hoi-Hung
HH
Chan
Hsiao-Mei
HM
Kuo
Li-Fen
LF
Liu
Tsung-Hui
TH
Hu
Cheuk-Kwan
CK
Sun
Mei-Lang
ML
Kung
Shih-Wei
SW
Lin
E-Ming
EM
Wang
Yi-Ling
YL
Ma
Kwan-Hung
KH
Cheng
Kwok Hung
KH
Lai
Zhi-Hong
ZH
Wen
Ping-I
PI
Hsu
Ming-Hong
MH
Tai
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000068579:Celecoxib; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D018450:Disease Progression; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D007124:Immunoenzyme Techniques; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
C497483:CD44 protein, human; D052246:Cyclooxygenase 2 Inhibitors; D018960:Hyaluronan Receptors; D047495:PPAR gamma; D011720:Pyrazoles; D012333:RNA, Messenger; D013449:Sulfonamides; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D000068579:Celecoxib; D015232:Dinoprostone