Curcumin suppresses constitutive activation of STAT-3 by up-regulating protein inhibitor of activated STAT-3 (PIAS-3) in ovarian and endometrial cancer cells.

Abstract

Signal transducer and activator of transcription-3 (STAT-3) is constitutively activated in ovarian and endometrial cancers and is implicated in uncontrolled cell growth. Thus, its disruption could be an effective approach to control tumorigenesis. Curcumin is a dihydroxyphenolic compound, with proven anti-cancer efficacy in various cancer models. We examined the anti-tumor mechanism of curcumin on STAT-3 and on the negative regulators of STAT-3, including suppressors of cytokine signaling proteins (SOCS-1 and SOCS-3), protein inhibitors of activated STAT (PIAS-1 and PIAS-3), and SH2 domain-containing phosphatases (SHP-1 and SHP-2) in ovarian and endometrial cancer cell lines. Treatment of cancer cells with curcumin induced a dose- and time-dependent decrease of constitutive IL-6 expression and of constitutive and IL-6-induced STAT-3 phosphorylation, which is associated with decreased cell viability and increased cleavage of caspase-3. The inhibition of STAT-3 activation by curcumin was reversible, and phosphorylated STAT-3 levels returned to control levels 24 h after curcumin removal. Compared to normal cells baseline expression of SOCS-3 was high in cancer cells and a marked decrease in SOCS-3 expression was seen following curcumin treatment. Overexpression of SOCS-3 in curcumin-treated cells increased expression of phosphorylated STAT-3 and resulted in increased cell viability. Normal ovarian and endometrial cells exhibited high expression of PIAS-3 protein, whereas in cancer cells the expression was greatly reduced. Curcumin increased PIAS-3 expression in cancer cells. Of significance, siRNA-mediated knockdown of PIAS-3 overcomes the inhibitory effect of curcumin on STAT-3 phosphorylation and cell viability. In conclusion, curcumin suppresses JAK-STAT signaling via activation of PIAS-3, thus attenuating STAT-3 phosphorylation and tumor cell growth.

• Authors: Manush Saydmohammed, Doina Joseph, Viqar Syed
• Journal: Journal of cellular biochemistry (J Cell Biochem) Vol. 110 Issue 2 Pg. 447-56 (May 15 2010) ISSN: 1097-4644 [Electronic] United States
• PMID: 20235152 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: (c) 2010 Wiley-Liss, Inc.

Chemical References

• Molecular Chaperones
• PIAS3 protein, human
• Protein Inhibitors of Activated STAT
• STAT3 Transcription Factor
• STAT3 protein, human
• Curcumin

Topics

• Apoptosis (drug effects)
• Blotting, Western
• Cell Line, Tumor
• Curcumin (pharmacology)
• Endometrial Neoplasms (metabolism, pathology)
• Female
• Humans
• Molecular Chaperones (metabolism)
• Ovarian Neoplasms (metabolism, pathology)
• Phosphorylation
• Protein Inhibitors of Activated STAT (metabolism)
• STAT3 Transcription Factor (antagonists & inhibitors, metabolism)
• Up-Regulation (physiology)