Gambogic acid inhibits STAT3 phosphorylation through activation of protein tyrosine phosphatase SHP-1: potential role in proliferation and apoptosis.
Gambogic acid inhibits STAT3 phosphorylation through activation of protein tyrosine phosphatase SHP-1: potential role in proliferation and apoptosis.
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DOI：
10.1158/1940-6207.capr-10-0340
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发表时间：
2011-07
期刊：
影响因子：
--
通讯作者：
Aggarwal BB
中科院分区：
文献类型：
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作者：
Prasad S;Pandey MK;Yadav VR;Aggarwal BB
转录因子信号转导子和转录激活子3（STAT 3）与癌细胞的增殖、存活和转移相关。我们研究了是否藤黄酸（GA），从传统中药，Gamboge hanburyi（山竹）的树脂衍生的氧杂蒽酮，可以调节STAT 3通路，导致抑制癌细胞的生长和敏化。我们发现GA诱导的人多发性骨髓瘤细胞凋亡与组成型和诱导型STAT 3激活的抑制相关。GA抑制STAT 3在酪氨酸残基705和丝氨酸残基727处的磷酸化。STAT 3抑制通过抑制蛋白酪氨酸激酶Janus激活激酶（JAK）1和JAK 2的激活来介导。用蛋白酪氨酸磷酸酶（PTP）抑制剂过钒酸盐治疗逆转了GA诱导的STAT 3下调，表明PTP的参与。我们还发现GA诱导PTP SHP-1的表达。通过小干扰RNA删除SHP-1基因抑制GA抑制STAT 3激活和诱导细胞凋亡的能力，表明SHP-1在其作用中的关键作用。此外，GA下调STAT 3调节的抗凋亡（Bcl-2，Bcl-xL和Mcl-1），增殖（细胞周期蛋白D1）和血管生成（VEGF）蛋白的表达，这与抑制增殖和诱导凋亡相关。总的来说，这些结果表明GA阻断STAT 3活化，导致肿瘤细胞增殖的抑制和凋亡的诱导。
The transcription factor, signal transducer and activator of transcription 3 (STAT3), is associated with proliferation, survival, and metastasis of cancer cells. We investigated whether gambogic acid (GA), a xanthone derived from the resin of traditional Chinese medicine, Gamboge hanburyi (mangosteen), can regulate the STAT3 pathway, leading to suppression of growth and sensitization of cancer cells. We found that GA induced apoptosis in human multiple myeloma cells that correlated with the inhibition of both constitutive and inducible STAT3 activation. STAT3 phosphorylation at both tyrosine residue 705 and serine residue 727 was inhibited by GA. STAT3 suppression was mediated through the inhibition of activation of the protein tyrosine kinases Janus-activated kinase (JAK) 1, and JAK2. Treatment with the protein tyrosine phosphatase (PTP) inhibitor pervanadate reversed the GA-induced down-regulation of STAT3, suggesting the involvement of a PTP. We also found that GA induced the expression of the PTP SHP-1. Deletion of the SHP-1 gene by small interfering RNA suppressed the ability of GA to inhibit STAT3 activation and to induce apoptosis, suggesting the critical role of SHP-1 in its action. Moreover, GA down-regulated the expression of STAT3-regulated antiapoptotic (Bcl-2, Bcl-xL, and Mcl-1), proliferative (cyclin D1), and angiogenic (VEGF) proteins, and this correlated with suppression of proliferation and induction of apoptosis. Overall, these results suggest that GA blocks STAT3 activation, leading to suppression of tumor cell proliferation and induction of apoptosis.