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. J. Cell. Biochem. 110: 447–456, 2010. © 2010 Wiley‐Liss, Inc.