Survivin is a downstream target and effector of sulindac-sensitive oncogenic Stat3 signalling in head and neck cancer.
Sulindac exerts its antitumorigenic effects in oral squamous cell carcinoma (SCC) cells by modulating survivin in a Stat3-dependent manner. Immunohistochemistry was used to detect the protein levels of phosphorylated-tyrosine Stat3 (p-tyr Stat3) and survivin in SCC tissues. Western blot, reverse transcriptase polymerase chain reaction, Annexin-V and cell proliferation assays were used to determine p-tyr Stat3 and survivin protein and mRNA expression, and cell viability following treatment with cyclooxygenase (COX) inhibitors, Stat3 siRNA, or the forced expression of Stat3 or survivin. Immunohistochemical analysis revealed an overexpression of p-tyr Stat3 in T1 SCCs. The importance of constitutive Stat3 activation in tumourigenesis was confirmed by siRNA inhibition of Stat3, resulting in cell growth inhibition and apoptosis, via a downregulation of survivin mRNA and protein expression. The forced expression of survivin partially reversed these effects of Stat3 inhibition. Sulindac, but not other COX inhibitors, downregulated Stat3, which correlated to an inhibition of cell proliferation, survival and survivin expression. Transfection of constitutively active Stat3 restored survivin expression and partially rescued SCC cells from sulindac-induced antitumorigenic effects. These data indicate that survivin is a downstream target and effector of oncogenic Stat3 signalling in SCC, which is targeted by sulindac in a COX-2-independent manner.
Scheper
M A
MA
Department of Diagnostic Sciences and Pathology, Dental School, University of Maryland, Baltimore, 650 W. Baltimore Ave. 7 North, Baltimore, MD 21201, USA. Mscheper@UMaryland.edu
Nikitakis
N G
NG
Sauk
J J
JJ
D017304:Annexin A5 / Q000032:analysis; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D000068579:Celecoxib; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D015853:Cysteine Proteinase Inhibitors / Q000032:analysis*; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000032:analysis; D006801:Humans; D007150:Immunohistochemistry; D007213:Indomethacin / Q000494:pharmacology; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000032:analysis / Q000187:drug effects*; D009363:Neoplasm Proteins / Q000032:analysis / Q000187:drug effects*; D011720:Pyrazoles / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000032:analysis / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology; D013467:Sulindac / Q000494:pharmacology*; D000077022:Survivin; D014062:Tongue Neoplasms / Q000473:pathology*; D014407:Tumor Cells, Cultured
D017304:Annexin A5; D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D052246:Cyclooxygenase 2 Inhibitors; D015853:Cysteine Proteinase Inhibitors; D004791:Enzyme Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D011720:Pyrazoles; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013449:Sulfonamides; D000077022:Survivin; D013467:Sulindac; D000068579:Celecoxib; C012655:nimesulide; D007213:Indomethacin