Cyclooxygenase-2 inhibition inhibits PI3K/AKT kinase activity in epithelial ovarian cancer.
Cyclooxygenase-2 (COX-2) expression contributes to tumor growth and invasion in epithelial ovarian cancer (EOC). COX-2 inhibitors exhibit important anticarcinogenic potential against EOC, but the molecular mechanisms underlying this effect and relation with PI3-kinase/AKT signaling remain the subject of intense investigations. Therefore, the role of COX-2 in EOC and its cross talk with PI3-kinase/AKT pathway were investigated using a large series of EOC tissues in a tissue micro array (TMA) format followed by in vitro and in vivo studies using EOC cell lines and NUDE mice. Clinically, COX-2 was overexpressed in 60.3% of EOC and was significantly associated with activated AKT (p < 0.0001). Cox-1 expression was seen in 59.9% but did not associate with AKT. Our in vitro data using EOC cell line showed that inhibition of COX-2 by aspirin, selective inhibitor NS398 and gene silencing by COX-2 specific siRNA impaired phosphorylation of AKT resulting decreased downstream signaling leading to cell growth inhibition and induction of apoptosis. Finally, treatment of MDAH2774 cell line xenografts with aspirin resulted in growth inhibition of tumors in NUDE mice via down-regulation of COX-2 and AKT activity. These data identify COX-2 as a potential biomarker and therapeutic target in distinct molecular subtypes of ovarian cancer.
Uddin
Shahab
S
King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. Shahab@KFSHRC.edu.sa
Ahmed
Maqbool
M
Hussain
Azhar
A
Assad
Lina
L
Al-Dayel
Fouad
F
Bavi
Prashant
P
Al-Kuraya
Khawla S
KS
Munkarah
Adnan
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001241:Aspirin / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009578:Nitrobenzenes / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000473:pathology* / Q000517:prevention & control; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D046888:Tissue Array Analysis; D023041:Xenograft Model Antitumor Assays
D001241:Aspirin; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D009578:Nitrobenzenes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; C496540:PTGS2 protein, human