Bozza William P, Zhang Yaqin, Hallett Kory, Rivera Rosado Leslie A, Zhang Baolin
Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA.
United States Public Health Service Commissioned Corps, Rockville, MD 20852, USA.
Oncotarget. 2015 Oct 20;6(32):32723-36. doi: 10.18632/oncotarget.5416.
Rho GDP Dissociation Inhibitor (RhoGDI) is a key regulator of Rho GTPases. Here we report that loss of RhoGDI significantly accelerated xenograft tumor growth of MDA-MB-231 cells in animal models. At the molecular level, RhoGDI depletion resulted in constitutive activation of Rho GTPases, including RhoA, Cdc42, and Rac1. This was accompanied by Rho GTPase translocation from the cytosol to membrane compartments. Notably, COX-2 protein levels, mRNA expression, and biological activity were markedly increased in RhoGDI-deficient cells. The upregulated expression of COX-2 was directly associated with increased Rho GTPase activity. Further, we assessed the expression level of RhoGDI protein in breast tumor specimens (n = 165) by immunohistochemistry. We found that RhoGDI expression is higher in the early stages of breast cancer followed by a significant decrease in malignant tumors and metastatic lesions (p < 0.01). These data suggest that downregulation of RhoGDI could be a critical mechanism of breast tumor development, which may involve the hyperactivation of Rho GTPases and upregulation of COX-2 activity. Additional studies are warranted to evaluate the therapeutic potential of inhibiting Rho GTPases and COX-2 for treating breast cancers.
Rho GDP解离抑制剂（RhoGDI）是Rho GTP酶的关键调节因子。在此我们报告，在动物模型中，RhoGDI的缺失显著加速了MDA-MB-231细胞的异种移植肿瘤生长。在分子水平上，RhoGDI的缺失导致Rho GTP酶的组成性激活，包括RhoA、Cdc42和Rac1。这伴随着Rho GTP酶从胞质溶胶向膜区室的易位。值得注意的是，在缺乏RhoGDI的细胞中，COX-2蛋白水平、mRNA表达和生物学活性均显著增加。COX-2表达上调与Rho GTP酶活性增加直接相关。此外，我们通过免疫组织化学评估了乳腺肿瘤标本（n = 165）中RhoGDI蛋白的表达水平。我们发现，RhoGDI在乳腺癌早期的表达较高，随后在恶性肿瘤和转移灶中显著降低（p < 0.01）。这些数据表明，RhoGDI的下调可能是乳腺肿瘤发生发展的关键机制，这可能涉及Rho GTP酶的过度激活和COX-2活性的上调。有必要进行进一步的研究来评估抑制Rho GTP酶和COX-2治疗乳腺癌的潜在疗效。
