GAP161 targets and downregulates G3BP to suppress cell growth and potentiate cisplaitin-mediated cytotoxicity to colon carcinoma HCT116 cells
GAP161 targets and downregulates G3BP to suppress cell growth and potentiate cisplaitin-mediated cytotoxicity to colon carcinoma HCT116 cells
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DOI：
10.1111/j.1349-7006.2012.02361.x
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发表时间：
2012-10-01
期刊：
影响因子：
5.7
通讯作者：
Shao, Rong-guang
中科院分区：
文献类型：
--
作者：
Zhang, Hao;Zhang, Shenghua;Shao, Rong-guang
Ras-GT3激活蛋白SH 3结构域结合蛋白（G3 BP）在多种人类肿瘤中过表达，并参与涉及生长、分化和凋亡的若干信号通路。G3 BP仅在生长细胞中与RasGAP（Ras-GTBP activating protein）相互作用，并依赖于Ras的激活，参与Ras信号通路。因此，阻断和下调G3 BP可能成为肿瘤治疗的新策略。在这份报告中，我们证明了一种新的肽GAP 161阻断G3 BP的功能，并通过诱导凋亡显着抑制HCT 116细胞的生长。该肽与G3 BP结合，干扰G3 BP 1与RasGAP的相互作用，并进一步抑制Ras信号通路。GAP 161下调G3 BP 1和G3 BP 2蛋白。同样，G3 BP的敲低显著降低了HCT 116细胞的增殖，并抑制了Ras信号通路。下调G3 BP表达可增强顺铂诱导的HCT 116细胞凋亡和生长抑制作用。我们还发现GAP 161抑制了携带结肠CT 26肿瘤的BALB/c小鼠和携带HCT 116异种移植物的裸鼠的生长。这些结果表明，下调G3 BP可能是有用的癌症治疗和GAP 161是一个有前途的新的治疗药物的癌症。（Cancer Sci，doi：10.1111/j.1349-7006.2012.02361.x，2012）
Ras-GTPase-activating protein SH3 domain-binding proteins (G3BP) are overexpressed in various human tumors and participate in several signaling pathways involved in growth, differentiation and apoptosis. G3BP interact with RasGAP (Ras-GTPase activating protein) only in growing cells and depend on Ras activation, and participate in the Ras signal pathway. Therefore, the blockage and downregulation of G3BP may be a new strategy for cancer therapy. In this report, we demonstrate that a novel peptide GAP161 blocked the functions of G3BP and markedly suppressed HCT116 cell growth through the induction of apoptosis. The peptide bound with G3BP, which interfered with the interaction of G3BP1 with RasGAP and further suppressed Ras signaling pathways. GAP161 downregulated G3BP1 and G3BP2 proteins. Similarly, the knockdown of G3BP substantially decreased the proliferation of HCT116 cells and inhibited Ras signal pathways. Furthermore, the downregulation of G3BP could enhance cisplatin-induced apoptosis and growth inhibition of HCT116 cells. We also found that GAP161 suppressed the growth of BALB/c mice bearing colon CT26 tumors and nude mice bearing HCT116 xenografts. These results suggest that downregulation of G3BP might be useful in cancer therapy and that GAP161 is a promising new therapeutic agent for cancers. (Cancer Sci, doi: 10.1111/j.1349-7006.2012.02361.x, 2012)