Direct inhibition of the transforming growth factor-β pathway by protein-bound polysaccharide through inactivation of Smad2 signaling
Direct inhibition of the transforming growth factor-β pathway by protein-bound polysaccharide through inactivation of Smad2 signaling
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DOI：
10.1111/j.1349-7006.2011.02133.x
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发表时间：
2012-02-01
期刊：
影响因子：
5.7
通讯作者：
Kitagawa, Yuko
中科院分区：
文献类型：
--
作者：
Ono, Yoshihiro;Hayashida, Tetsu;Kitagawa, Yuko
转化生长因子-β参与细胞增殖、分化和凋亡的调节，与上皮间充质转化(EMT)有关。抑制转化生长因子-β途径是治疗癌症的一种有吸引力的策略。我们最近在商业上可用的药物中筛选出新的转化生长因子-β抑制剂，并确定蛋白结合多糖(PSK)是转化生长因子-β1反应的荧光素酶报告因子3TP-lux诱导的报告活性的强烈抑制物。在日本，蛋白质结合的多糖被用作治疗胃癌和结直肠癌的非特异性免疫刺激剂。该制剂的抗癌活性除具有免疫调节作用外，还可能直接调节肿瘤中生长因子的产生和酶的活性。虽然已有多项临床研究表明PSK对各种类型的肿瘤有有益的治疗作用，但其作用机制尚不清楚。在本研究中，Western印迹分析表明，PSK抑制了Smad2蛋白的磷酸化和核定位，从而表明PSK抑制了Smad和MAPK通路。定量聚合酶链式反应分析显示，PSK降低了多个转化生长因子-β途径靶基因的表达。E-钙粘蛋白和波形蛋白免疫组织化学显示PSK抑制转化生长因子-β1诱导的EMT，流式细胞仪分析显示PSK抑制EMT介导的CD44+/CD24-细胞的产生。这些数据为PSK介导转化生长因子-β抑制活性的机制提供了新的见解，并提示PSK可以有效地治疗与转化生长因子-β信号转导相关的疾病。(《癌症科学》2012年版，第103期：317324页)
Transforming growth factor-beta (TGF-beta) is involved in the regulation of cell proliferation, differentiation, and apoptosis and is associated with epithelialmesenchymal transition (EMT). Inhibition of the TGF-beta pathway is an attractive strategy for the treatment of cancer. We recently screened for novel TGF-beta inhibitors among commercially available drugs and identified protein-bound polysaccharide (PSK) as a strong inhibitor of the TGF-beta-induced reporter activity of 3TP-lux, a TGF-beta 1-responsive luciferase reporter. Protein-bound polysaccharide is used as a non-specific immunostimulant for the treatment of gastric and colorectal cancers in Japan. The anticancer activity of this agent may involve direct regulation of growth factor production and enzyme activity in tumors in addition to its immunomodulatory effect. Although several clinical studies have shown the beneficial therapeutic effects of PSK on various types of tumors, its mechanism of action is not clear. In the present study, Western blot analysis showed that PSK suppressed the phosphorylation and nuclear localization of the Smad2 protein, thereby suggesting that PSK inhibits the Smad and MAPK pathways. Quantitative PCR analysis showed that PSK decreased the expression of several TGF-beta pathway target genes. E-cadherin and vimentin immunohistochemistry showed that PSK suppressed TGF-beta 1-induced EMT, and FACS analysis showed that PSK inhibited the EMT-mediated generation of CD44+/CD24- cells. These data provide new insights into the mechanisms mediating the TGF-beta-inhibiting activity of PSK and suggest that PSK can effectively treat diseases associated with TGF-beta signaling. (Cancer Sci 2012; 103: 317324)