Department of Microbiology/Research Institute of Life Science, College of Natural Sciences, Gyeongsang National University, Jinju, Republic of Korea.
Cancer Lett. 2011 Dec 1;311(1):48-56. doi: 10.1016/j.canlet.2011.06.024. Epub 2011 Jun 24.
Rho GDP dissociation inhibitor (RhoGDI)2 has been identified as a regulator of Rho family GTPase. Recently, we suggested that RhoGDI2 could promote tumor growth and malignant progression in gastric cancer. In this study, we demonstrate that RhoGDI2 contributes to another important feature of aggressive cancers, i.e., resistance to chemotherapeutic agents such as cisplatin. Forced expression of RhoGDI2 attenuated cisplatin-induced apoptosis, whereas RhoGDI2 depletion showed opposite effects in vitro. Moreover, the increased anti-apoptotic effect of RhoGDI2 on cisplatin was further validated in RhoGDI2-overexpressing SNU-484 xenograft model in nude mice. Furthermore, we identified Bcl-2 as a major determinant of RhoGDI2-mediated cisplatin resistance in gastric cancer cells. Depletion of Bcl-2 expression significantly increased cisplatin-induced apoptosis in RhoGDI2-overexpressing gastric cancer cells, whereas overexpression of Bcl-2 blocked cisplatin-induced apoptosis in RhoGDI2-depleted gastric cancer cells. Overall, these findings establish RhoGDI2 as an important therapeutic target for simultaneously enhancing chemotherapy efficacy and reducing metastasis risk in gastric cancer.
Rho GDP 解离抑制剂（RhoGDI）2 已被鉴定为 Rho 家族 GTPase 的调节剂。最近，我们提出 RhoGDI2 可能促进胃癌的肿瘤生长和恶性进展。在这项研究中，我们证明 RhoGDI2 有助于侵袭性癌症的另一个重要特征，即对顺铂等化疗药物的耐药性。强制表达 RhoGDI2 减弱了顺铂诱导的细胞凋亡，而 RhoGDI2 耗竭则在体外表现出相反的效果。此外，在 RhoGDI2 过表达的 SNU-484 裸鼠异种移植模型中进一步验证了 RhoGDI2 对顺铂的增加的抗凋亡作用。此外，我们确定 Bcl-2 是 RhoGDI2 介导的胃癌细胞对顺铂耐药的主要决定因素。Bcl-2 表达的耗竭显著增加了 RhoGDI2 过表达的胃癌细胞中顺铂诱导的细胞凋亡，而 Bcl-2 的过表达则阻断了 RhoGDI2 耗尽的胃癌细胞中顺铂诱导的细胞凋亡。总的来说，这些发现确立了 RhoGDI2 作为同时增强化疗效果和降低胃癌转移风险的重要治疗靶点。
