Small Molecule APY606 Displays Extensive Antitumor Activity in Pancreatic Cancer via Impairing Ras-MAPK Signaling.
Small Molecule APY606 Displays Extensive Antitumor Activity in Pancreatic Cancer via Impairing Ras-MAPK Signaling.
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小分子 APY606 通过削弱 Ras-MAPK 信号传导在胰腺癌中表现出广泛的抗肿瘤活性
DOI：
10.1371/journal.pone.0155874
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Guo N;Liu Z;Zhao W;Wang E;Wang J
胰腺癌中存在Ras蛋白的异常表达或突变。致癌性Ras激活利用其广泛的信号传导范围影响多个细胞过程，其中丝裂原活化蛋白激酶（MAPK）信号传导在肿瘤发生中发挥重要作用。因此，靶向Ras的治疗对胰腺癌具有主要益处。基于Ras靶点受体的虚拟药物筛选已成功筛选出小分子APY 606，但其深入作用机制仍有待阐明。本研究以人胰腺癌细胞株Capan-1和SW 1990为靶细胞，观察APY 606的抗肿瘤活性，并探讨Ras-MAPK和凋亡相关信号通路对APY 606活性的影响。APY 606处理导致癌细胞活力的剂量和时间依赖性抑制。此外，APY 606还表现出较强的抗肿瘤活性，不仅可以减少肿瘤细胞的侵袭、迁移和线粒体膜电位，还可以改变多个细胞凋亡指数。APY 606还可直接抑制Ras-GTP和下游MAPK的激活，导致抗凋亡蛋白Bcl-2表达下调，线粒体凋亡途径相关蛋白Bax、细胞色素c和Caspase 3表达上调，细胞周期蛋白依赖性激酶2和细胞周期蛋白A、E表达上调。这些数据表明，在胰腺癌的治疗干预期间，损害Ras-MAPK信号传导是APY 606的一种新的作用机制。
Pancreatic cancer has been found with abnormal expression or mutation in Ras proteins. Oncogenic Ras activation exploits their extensive signaling reach to affect multiple cellular processes, in which the mitogen-activated protein kinase (MAPK) signaling exerts important roles in tumorigenesis. Therapies targeted Ras are thus of major benefit for pancreatic cancer. Although small molecule APY606 has been successfully picked out by virtual drug screening based on Ras target receptor, its in-depth mechanism remains to be elucidated. We herein assessed the antitumor activity of APY606 against human pancreatic cancer Capan-1 and SW1990 cell lines and explored the effect of Ras-MAPK and apoptosis-related signaling pathway on the activity of APY606. APY606 treatment resulted in a dose- and time-dependent inhibition of cancer cell viability. Additionally, APY606 exhibited strong antitumor activity, as evidenced not only by reduction in tumor cell invasion, migration and mitochondrial membrane potential but also by alteration in several apoptotic indexes. Furthermore, APY606 treatment directly inhibited Ras-GTP and the downstream activation of MAPK, which resulted in the down-regulation of anti-apoptotic protein Bcl-2, leading to the up-regulation of mitochondrial apoptosis pathway-related proteins (Bax, cytosolic Cytochrome c and Caspase 3) and of cyclin-dependent kinase 2 and Cyclin A, E. These data suggest that impairing Ras-MAPK signaling is a novel mechanism of action for APY606 during therapeutic intervention in pancreatic cancer.