Wang Gang, Jing Yue, Cao Lingsen, Gong Changchang, Gong Zhunan, Cao Xiangrong
Center for New Drug Research and Development, College of Life Science, Nanjing Normal University.
Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University.
Onco Targets Ther. 2016 Dec 20;10:55-66. doi: 10.2147/OTT.S121619. eCollection 2017.
Activation of the transcription factor, signal transducers and activators of transcription 3 (STAT3), has been linked to the proliferation and migration of a variety of human cancer cells. These actions occur via the upregulation or downregulation of cell survival and tumor suppressor genes, respectively. Importantly, agents that can suppress STAT3 activation have the potential for use in the prevention and treatment of various cancers. In this study, an Asiatic acid (AA) derivative, -(2α,3β,23-acetoxyurs-12-en-28-oyl)-l-proline methyl ester (AA-PMe), is reported to dose dependently suppress constitutive STAT3 activation in gastric cancer cells. This inhibition was mediated by blockade of Janus-activated kinase 2. Additionally, AA-PMe regulated the expression of STAT3-modulated gene products, including cyclin D1, Bax, Bcl-2, c-Myc, and matrix metalloproteinase (MMP)-2 and MMP-9. Finally, transfection with both a STAT3 mimic and an inhibitor reversed the AA-PMe-driven modulation of STAT3 downstream gene products. Overall, these results suggest that AA-PMe is a novel blocker of STAT3 activation and has the potential for the prevention and treatment of gastric cancer.
转录因子信号转导子与转录激活子3（STAT3）的激活与多种人类癌细胞的增殖和迁移有关。这些作用分别通过上调或下调细胞存活和肿瘤抑制基因来实现。重要的是，能够抑制STAT3激活的药物具有用于预防和治疗各种癌症的潜力。在本研究中，据报道一种齐墩果酸（AA）衍生物，-(2α,3β,23-乙酰氧基乌苏-12-烯-28-酰基)-L-脯氨酸甲酯（AA-PMe）能剂量依赖性地抑制胃癌细胞中组成型STAT3的激活。这种抑制作用是通过阻断Janus激活激酶2介导的。此外，AA-PMe调节了STAT3调控的基因产物的表达，包括细胞周期蛋白D1、Bax、Bcl-2、c-Myc以及基质金属蛋白酶（MMP）-2和MMP-9。最后，用STAT3模拟物和抑制剂进行转染可逆转AA-PMe对STAT3下游基因产物的调控。总体而言，这些结果表明AA-PMe是一种新型的STAT3激活阻滞剂，具有预防和治疗胃癌的潜力。
