Gossypol induces apoptosis in multiple myeloma cells by inhibition of interleukin-6 signaling and Bcl-2/Mcl-1 pathway.
Gossypol induces apoptosis in multiple myeloma cells by inhibition of interleukin-6 signaling and Bcl-2/Mcl-1 pathway.
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DOI：
10.3892/ijo.2014.2652
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发表时间：
2014-12
影响因子：
5.2
通讯作者：
Kizaki M
中科院分区：
文献类型：
--
作者：
Sadahira K;Sagawa M;Nakazato T;Uchida H;Ikeda Y;Okamoto S;Nakajima H;Kizaki M
多发性骨髓瘤(MM)是一种影响免疫系统的克隆性浆细胞疾病，具有多种全身症状。即使使用常规药物进行大剂量化疗，多发性骨髓瘤仍然无法治愈，因此有必要开发新的治疗策略。棉酚是从棉花中提取的一种天然多酚类化合物，已被证明具有抗多种肿瘤活性。最近的研究表明，GOS是一种BH3类似物，可以作为BH3的模拟物，干扰促凋亡的BH3-Only蛋白与Bcl2/Bclxl之间的相互作用，是一种Bcl2或Bclxl的抑制剂。由于大多数MM患者过表达Bcl2蛋白，我们认为GOS可能是治疗MM的一种有前景的药物。我们的研究表明，GOS以剂量和时间依赖的方式有效地诱导OPM2 MM细胞株的凋亡和抑制其增殖。GOS诱导线粒体caspase-3的激活和细胞色素c的释放，表明线粒体功能障碍途径在细胞凋亡过程中起作用。进一步的研究表明，GoS处理可减弱细胞内丝氨酸-70处Bcl2的磷酸化，而蛋白质水平不受影响。此外，Mcl-1被GOS下调。有趣的是，JAK2、STAT3、ERK1/2和p38MAPK的磷酸化被GOS处理抑制，这表明GOS整体上抑制了IL-6信号。此外，JAK2的抑制作用类似于GOS对OPM2细胞的作用，包括Bcl2去磷酸化和Mcl-1下调。这些结果表明，GOS不仅通过取代BH3-Only蛋白来诱导MM细胞的凋亡，而且还通过抑制IL-6信号转导导致Bcl2去磷酸化和Mcl-1下调而诱导MM细胞的凋亡。
Multiple myeloma (MM) is a clonal plasma cell disorder affecting the immune system with various systemic symptoms. MM remains incurable even with high dose chemotherapy using conventional drugs, thus necessitating development of novel therapeutic strategies. Gossypol (Gos) is a natural polyphenolic compound extracted from cotton plants, and has been shown to possess anti-neoplastic activity against various tumors. Recent studies have shown that Gos is an inhibitor for Bcl-2 or Bcl-XL acting as BH3 mimetics that interfere interaction between pro-apoptotic BH3-only proteins and Bcl-2/Bcl-XL. Since most of the patients with MM overexpress Bcl-2 protein, we considered Gos might be a promising therapeutic agent for MM. We herein show that Gos efficiently induced apoptosis and inhibited proliferation of the OPM2 MM cell line, in a dose- and time-dependent manner. Gos induced activation of caspase-3 and cytochrome c release from mitochondria, showing mitochondrial dysfunction pathway is operational during apoptosis. Further investigation revealed that phosphorylation of Bcl-2 at serine-70 was attenuated by Gos treatment, while protein levels were not affected. In addition, Mcl-1 was downregulated by Gos. Interestingly, phosphorylation of JAK2, STAT3, ERK1/2 and p38MAPK was inhibited by Gos-treatment, indicating that Gos globally suppressed interleukin-6 (IL-6) signals. Moreover, JAK2 inhibition mimicked the effect of Gos in OPM2 cells including Bcl-2 dephosphorylation and Mcl-1 downregulation. These results demonstrated that Gos induces apoptosis in MM cells not only through displacing BH3-only proteins from Bcl-2, but also through inhibiting IL-6 signaling, which leads to Bcl-2 dephosphorylation and Mcl-1 downregulation.
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