Guggulsterone, a farnesoid X receptor antagonist, inhibits constitutive and inducible STAT3 activation through induction of a protein tyrosine phosphatase SHP-1 (Publication with Expression of Concern. See vol. 78, pg. 5184, 2018)
Guggulsterone, a farnesoid X receptor antagonist, inhibits constitutive and inducible STAT3 activation through induction of a protein tyrosine phosphatase SHP-1 (Publication with Expression of Concern. See vol. 78, pg. 5184, 2018)
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DOI：
10.1158/0008-5472.can-07-6696
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发表时间：
2008-06-01
期刊：
影响因子：
11.2
通讯作者：
Aggarwal, Bharat B.
中科院分区：
文献类型：
--
作者：
Ahn, Kwang Seok;Sethi, Gautam;Aggarwal, Bharat B.
信号转导和转录激活子3(STAT3)是一种转录因子，与肿瘤细胞的存活、增殖、化疗耐药和血管生成有关。研究了法尼醇X受体拮抗剂谷固酮(GS)的抗凋亡、抗增殖和抗肿瘤转移作用是否与其抑制STAT3激活的能力有关。我们发现，GS的Z立体异构体而不是E立体异构体抑制了结构性和白介素6诱导的人多发性骨髓瘤细胞中STAT3的激活。STAT3的抑制是通过抑制蛋白酪氨酸激酶Janus激活的激酶2和c-Src的激活而实现的。钒酸盐处理逆转了GS诱导的STAT3下调，这表明蛋白酪氨酸磷酸酶参与了这一过程。事实上，我们发现GS诱导了酪氨酸蛋白磷酸酶SHP-1的蛋白和mRNA的表达，这并不是由于SHP-1启动子的去甲基化导致了SHP-1的表观遗传沉默。此外，SHP-1被小干扰RNA敲除后，GS对SHP-1的诱导作用和对STAT3活性的抑制作用被抑制，从而提示SHP-1参与了GS的作用。最后，GS下调STAT3调节的抗凋亡基因(Bcl2、Bclxl和Mcl-1)、增殖基因(CyClinD1)和血管生成基因(VEGF)的表达，这与抑制细胞增殖、细胞聚集在细胞周期的亚G(1)期和诱导细胞凋亡有关。总体而言，这些结果表明GS是一种新的STAT3激活阻滞剂，因此可能在调节肿瘤细胞的生长和转移方面具有潜力。
Signal transducers and activator of transcription 3 (STAT3) is a transcription factor that has been associated with survival, proliferation, chemoresistance, and angiogenesis of tumor cells. Whether the apoptotic, antiproliferative, and antimetastatic effects of guggulsterone (GS), a farnesoid X receptor antagonist, are linked to its ability to suppress STAT3 activation was investigated. We found that the Z but not the E stereoisomer of GS inhibited both constitutive and interleukin-6-induced STAT3 activation in human multiple myeloma cells. The suppression of STAT3 was mediated through the inhibition of activation of protein tyrosine kinases Janus-activated kinase 2 and c-Src. Vanadate treatment reversed the GS-induced down-regulation of STAT3, suggesting the involvement of a protein tyrosine phosphatase. Indeed, we found that GS induced the expression of both the protein an mRNA for tyrosine protein phosphatase SHP-1 that was not due to demethylation of the SHP-1 promoter previously implicated in the epigenetic silencing of SHP-1. Moreover, knockdown of SHP-1 by small interfering RNA suppressed the effect of GS on induction of SHP-1 and on the inhibition of STAT3 activation, thereby implicating SHP-1 in the action of GS. Finally, GS down-regulated the expression of STAT3-regulated antiapoptotic (Bcl-2 Bcl-xL, and Mcl-1), proliferative (cyclin D1), and angiogenic (VEGF) gene products; and this correlated with suppression of proliferation, the accumulation of cells in sub-G(1) phase of cell cycle, and induction of apoptosis. Overall, these results suggest that GS is a novel blocker of STAT3 activation and thus may have a potential in regulation of growth and metastasis of tumor cells.