Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814-4799, USA.
J Cell Biochem. 2010 May 15;110(2):447-56. doi: 10.1002/jcb.22558.
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.
信号转导子和转录激活子 3（STAT-3）在卵巢癌和子宫内膜癌中持续激活，并与不受控制的细胞生长有关。因此，破坏它可能是控制肿瘤发生的有效方法。姜黄素是一种二羟基酚类化合物，在各种癌症模型中已被证明具有抗癌功效。我们研究了姜黄素对 STAT-3 及其负调控因子的抗肿瘤机制，包括细胞因子信号转导蛋白抑制剂（SOCS-1 和 SOCS-3）、激活 STAT 的蛋白抑制剂（PIAS-1 和 PIAS-3）和 SH2 结构域含磷酸酶（SHP-1 和 SHP-2），在卵巢癌和子宫内膜癌细胞系中。用姜黄素处理癌细胞可诱导组成型 IL-6 表达和组成型及 IL-6 诱导的 STAT-3 磷酸化的剂量和时间依赖性降低，这与细胞活力降低和 caspase-3 切割增加有关。姜黄素抑制 STAT-3 激活是可逆的，姜黄素去除 24 小时后磷酸化 STAT-3 水平恢复到对照水平。与正常细胞相比，SOCS-3 在癌细胞中的基础表达较高，姜黄素处理后 SOCS-3 表达明显降低。在姜黄素处理的细胞中过表达 SOCS-3 会增加磷酸化 STAT-3 的表达，并导致细胞活力增加。正常卵巢和子宫内膜细胞中 PIAS-3 蛋白表达较高，而在癌细胞中表达大大降低。姜黄素增加了癌细胞中 PIAS-3 的表达。重要的是，siRNA 介导的 PIAS-3 敲低克服了姜黄素对 STAT-3 磷酸化和细胞活力的抑制作用。总之，姜黄素通过激活 PIAS-3 抑制 JAK-STAT 信号转导，从而减弱 STAT-3 磷酸化和肿瘤细胞生长。
