Curcumin Suppresses Constitutive Activation of STAT-3 by Up-Regulating Protein Inhibitor of Activated STAT-3 (PIAS-3) in Ovarian and Endometrial Cancer Cells
Curcumin Suppresses Constitutive Activation of STAT-3 by Up-Regulating Protein Inhibitor of Activated STAT-3 (PIAS-3) in Ovarian and Endometrial Cancer Cells
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DOI：
10.1002/jcb.22558
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发表时间：
2010-05-15
影响因子：
4
通讯作者：
Syed, Viqar
中科院分区：
文献类型：
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作者：
Saydmohammed, Manush;Joseph, Doina;Syed, Viqar
信号转导器和转录激活剂 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，在多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 和 STAT-3 负调节因子的抗肿瘤机制，包括细胞因子信号蛋白的抑制因子（SOCS-1 和 SOCS-3）、活化 STAT 的蛋白质抑制剂（PIAS-1 和 PIAS-3）以及卵巢和子宫内膜癌细胞系中含有 SH2 结构域的磷酸酶（SHP-1 和 SHP-2）。用姜黄素处理癌细胞会诱导组成型 IL-6 表达以及组成型和 IL-6 诱导的 STAT-3 磷酸化呈剂量和时间依赖性下降，这与细胞活力下降和 caspase-3 裂解增加有关。姜黄素对 STAT-3 激活的抑制是可逆的，去除姜黄素后磷酸化的 STAT-3 水平恢复到对照水平 2411。与正常细胞相比，癌细胞中 SOCS-3 的基线表达较高，并且在姜黄素治疗后发现 SOCS-3 表达显着下降。姜黄素处理的细胞中 SOCS-3 的过度表达增加了磷酸化 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表现出PIAS-3蛋白的高表达，而在癌细胞中表达大大降低。姜黄素增加癌细胞中 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 信号传导，从而减弱 STAT-3 磷酸化和肿瘤细胞生长。 J.细胞。生物化学。 110: 447-456, 2010。(C) 2010 Wiley-Liss, Inc.
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 2411 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. (C) 2010 Wiley-Liss, Inc.