Ursolic acid inhibits STAT3 activation pathway leading to suppression of proliferation and chemosensitization of human multiple myeloma cells (Publication with Expression of Concern. See vol. 16, pg. 1442, 2018)
Ursolic acid inhibits STAT3 activation pathway leading to suppression of proliferation and chemosensitization of human multiple myeloma cells (Publication with Expression of Concern. See vol. 16, pg. 1442, 2018)
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DOI：
10.1158/1541-7786.mcr-06-0348
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发表时间：
2007-09-01
影响因子：
5.2
通讯作者：
Aggarwal, Bharat B.
中科院分区：
文献类型：
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作者：
Pathak, Ashutosh K.;Bhutani, Manisha;Aggarwal, Bharat B.
信号转导和转录激活子3(STAT3)的激活与多种人类癌细胞的增殖有关，包括多发性骨髓瘤。能够抑制STAT3激活的药物有预防和治疗癌症的潜力。在本报告中，我们测试了一种名为熊果酸的试剂，它存在于罗勒、苹果、李子和小红莓中，用于抑制STAT3的激活。我们发现，乌索酸，一种五环三萜类化合物，以剂量和时间依赖的方式抑制多发性骨髓瘤细胞中结构性和间接素-6诱导的STAT3激活。这种抑制是通过抑制上游的c-Src、Janus激活的激酶1、Janus激活的激酶2和细胞外信号调节的激酶1/2的激活来实现的。钒酸处理逆转了熊果酸诱导的STAT3的下调，这可能与酪氨酸磷酸酶有关。事实上，我们发现熊果酸诱导了酪氨酸磷酸酶SHP-1蛋白和mRNA的表达。此外，小干扰RNA对SHP-1的阻断抑制了SHP-1的诱导，并逆转了对STAT3激活的抑制，从而表明SHP-1在该三萜的作用中起着关键作用。熊果酸下调STAT3调控基因产物的表达，如细胞周期蛋白131、Bcl-2、Bcl-xl、Survivin、Mcl-1和血管内皮生长因子。熊果酸抑制细胞增殖，诱导细胞凋亡，使细胞聚集于细胞周期的G(1)-G(0)期。这种三萜类化合物还显著增强了沙利度胺和硼替佐米对多发性骨髓瘤细胞的凋亡作用。总体而言，这些结果表明熊果酸是一种新的STAT3激活阻滞剂，可能在预防和治疗多发性骨髓瘤和其他癌症方面具有潜力。
The activation of signal transducers and activators of transcription 3 (STAT3) has been linked with the proliferation of a variety of human cancer cells, including multiple myeloma. Agents that can suppress STAT3 activation have potential for prevention and treatment of cancer. In the present report, we tested an agent, ursolic acid, found in basil, apples, prunes, and cranberries, for its ability to suppress STAT3 activation. We found that ursolic acid, a pentacyclic triterpenoid, inhibited both constitutive and interieukin-6-inducible STAT3 activation in a dose- and time-dependent manner in multiple myeloma cells. The suppression was mediated through the inhibition of activation of upstream kinases c-Src, Janus-activated kinase 1, Janus-activated kinase 2, and extracellular signal-regulated kinase 1/2. Vanadate treatment reversed the ursolic acid-induced down-regulation of STAT3, suggesting the involvement of a tyrosine phosphatase. Indeed, we found that ursolic acid induced the expression of tyrosine phosphatase SHP-1 protein and mRNA. Moreover, knockdown of SHP-1 by small interfering RNA suppressed the induction of SHP-1 and reversed the inhibition of STAT3 activation, thereby indicating the critical role of SHP-1 in the action of this triterpene. Ursolic acid down-regulated the expression of STAT3-regulated gene products such as cyclin 131, Bcl-2, Bcl-xL, survivin, Mcl-1, and vascular endothelial growth factor. Finally, ursolic acid inhibited proliferation and induced apoptosis and the accumulation of cells in G(1)-G(0) phase of cell cycle. This triterpenoid also significantly Potentiated the apoptotic effects of thalidomide and bortezomib in multiple myeloma cells. Overall, these results suggest that ursolic acid is a novel blocker of STAT3 activation that may have a potential in prevention and treatment of multiple myeloma and other cancers.