Abstract
The nonsteroidal anti-inflammatory drug sulindac exerts a significant antineoplastic effect on several types of human cancers including oral squamous cell carcinoma (SCCa). Because constitutive activation of signal transducer and activator of transcription 3 (Stat3) has been linked to carcinogenesis of various tumors including head and neck SCCa, we studied whether sulindac treatment affects the Stat3 signaling pathway in oral SCCa cells. Western blot experiments showed that short-term treatment of cells with sulindac resulted in a large reduction of phosphorylated Stat3, without significantly affecting Stat3 protein levels. In contrast, 3 days of sulindac treatment eliminated both phosphorylated and unphosphorylated Stat3 protein levels. Also, sulindac treatment exerted a significant time-dependent cell growth-inhibitory effect on oral SCCa cells under the same conditions shown to induce Stat3 down-modulation. The sulfone metabolite of sulindac, which lacks cyclooxygenase-inhibitory activity, did not affect either Stat3 expression or Stat3 phosphorylation. Antisense oligonucleotide treatment against peroxisome proliferator-activated receptor gamma did not attenuate the ability of sulindac to down-regulate Stat3. Our results suggest that down-modulation of Stat3 can be induced by sulindac treatment, thus possibly contributing to the antineoplastic effect of this drug.
MeSH terms
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
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Antineoplastic Agents / pharmacology*
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Carcinoma, Squamous Cell / drug therapy
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Carcinoma, Squamous Cell / genetics
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Carcinoma, Squamous Cell / metabolism*
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Carcinoma, Squamous Cell / pathology
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Cell Division / drug effects
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DNA-Binding Proteins / antagonists & inhibitors*
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Down-Regulation / drug effects
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Humans
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Mouth Neoplasms / drug therapy
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Mouth Neoplasms / genetics
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Mouth Neoplasms / metabolism*
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Mouth Neoplasms / pathology
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Oligonucleotides, Antisense / pharmacology
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Phosphorylation / drug effects
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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Receptors, Cytoplasmic and Nuclear / biosynthesis
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Receptors, Cytoplasmic and Nuclear / genetics
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Reverse Transcriptase Polymerase Chain Reaction
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STAT3 Transcription Factor
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Signal Transduction / drug effects
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Sulindac / pharmacology*
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Trans-Activators / antagonists & inhibitors*
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Trans-Activators / biosynthesis
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Trans-Activators / genetics
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Trans-Activators / metabolism
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Transcription Factors / biosynthesis
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Transcription Factors / genetics
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Tumor Cells, Cultured
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Antineoplastic Agents
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DNA-Binding Proteins
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Oligonucleotides, Antisense
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RNA, Messenger
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Receptors, Cytoplasmic and Nuclear
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STAT3 Transcription Factor
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STAT3 protein, human
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Trans-Activators
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Transcription Factors
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Sulindac