The oncogenic effects of constitutive Stat3 signaling in salivary gland cancer cells are mediated by survivin and modulated by the NSAID sulindac.
OBJECTIVE
Constitutive activation of the signal transducer and activator of transcription 3 (Stat3) has been detected in various human cancers and has been linked to tumor development and progression. Oncogenic Stat3 signaling results in induction of specific target genes, among which survivin is implicated in the proliferation and survival of cancer cells. Targeting of Stat3 constitutive expression by the nonsteroidal antiinflammatory drug (NSAID) sulindac has been demonstrated to exert antineoplastic effects in oral squamous cell carcinoma cells in vitro and in vivo.


METHODS
The expression and functional role of Stat3 and survivin was evaluated in 2 salivary gland adenocarcinoma cell lines (HSY and HSG). In addition, the effects of the NSAID sulindac and other cyclooxygenase (COX) inhibitors on Stat3 and survivin expression and on cell proliferation and apoptosis of HSY and HSG cells were analyzed.


RESULTS
Messenger RNA and protein expression of Stat3 and survivin was detected in HSY and HSG cell lines. Treatment of these cells with siRNA against Stat3 or survivin inhibited cell proliferation and induced apoptosis. Moreover, Stat3 siRNA treatment down-regulated the protein and mRNA expression of survivin, and survivin forced expression partially reversed the antineoplastic effects of Stat3 siRNA treatment. Treatment of HSY and HSG cells with the NSAID sulindac, but not other COX inhibitors, induced significant decreases in cell proliferation and increases in apoptosis, accompanied by down-regulation of Stat3 and survivin expression. In contrast, survivin forced expression or transfection with constitutively active Stat3 attenuated the effects of sulindac on cell growth and apoptosis.


CONCLUSIONS
Taken together, these data support the importance of the constitutive Stat3 signaling for growth and survival of salivary gland cancer cells through the induction of survivin. Inhibition of the oncogenic Stat3-survivin pathway in these cells can be achieved by selective targeting techniques or treatment with the NSAID sulindac and holds promise for the treatment of salivary gland cancer.
Nikitakis
Nikolaos G
NG
Department of Oral Pathology and Medicine, School of Dentistry, National and Kapodistrian University of Athens, Athens, Greece. nnikitakis1@yahoo.com
Scheper
Mark A
MA
Papanikolaou
Vasileios S
VS
Sauk
John J
JJ
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D050796:STAT3 Transcription Factor / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D012468:Salivary Gland Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013467:Sulindac / Q000494:pharmacology; D000077022:Survivin
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D016861:Cyclooxygenase Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D000077022:Survivin; D013467:Sulindac