RhoA mediates cyclooxygenase-2 signaling to disrupt the formation of adherens junctions and increase cell motility
RhoA mediates cyclooxygenase-2 signaling to disrupt the formation of adherens junctions and increase cell motility
复制标题
DOI：
10.1158/0008-5472.can-06-1818
复制
发表时间：
2006-12-15
期刊：
影响因子：
11.2
通讯作者：
Jakobi, Rolf
中科院分区：
文献类型：
--
作者：
Chang, Yu-Wen E.;Marlin, Jerry W.;Jakobi, Rolf
环氧合酶-2（考克斯-2）是治疗和预防结直肠癌的重要靶点。虽然考克斯-2信号转导参与促进肿瘤细胞生长和侵袭，但介导这些过程的分子机制在很大程度上是未知的。在这项研究中，我们表明，RhoA途径介导的考克斯-2信号破坏粘附连接的形成，并增加细胞运动。粘附连接的破坏促进肿瘤细胞侵袭和转移，并且通常与肿瘤进展相关。我们在组成型表达考克斯-2的HCA-7结肠癌细胞中检测到高水平的RhoA活性。抑制考克斯-2显著降低HCA-7细胞中RhoA活性水平，表明组成型表达考克斯-2刺激RhoA活性。有趣的是，用小干扰RNA（siRNA）抑制考克斯-2或沉默考克斯-2表达刺激粘附连接的形成，伴随着E-钙粘蛋白和α-连环蛋白的蛋白水平增加。此外，用siRNA抑制RhoA或沉默RhoA表达增加了L-钙粘蛋白和α-连环蛋白的水平。抑制Rho激酶（ROCK），RhoA效应蛋白，也增加了E-钙粘蛋白和α-连环蛋白的水平，并刺激形成粘附连接。抑制考克斯-2或RhoA可显著降低HCA-7细胞的运动能力。因此，我们的数据揭示了一种新的分子机制，该机制将考克斯-2信号传导与破坏粘附连接的形成联系起来;考克斯-2刺激RhoA/ROCK通路，从而降低E-钙粘蛋白和α-连环蛋白的水平，导致粘附连接形成的破坏和运动性的增加。了解促进肿瘤进展的考克斯-2下游信号通路对于开发新的治疗策略至关重要。
Cyclooxygenase-2 (COX-2) represents an important target for treatment and prevention of colorectal cancer. Although COX-2 signaling is implicated in promoting tumor cell growth and invasion, the molecular mechanisms that mediate these processes are largely unknown. In this study, we show that the RhoA pathway mediates COX-2 signaling to disrupt the formation of adherens junctions and increase cell motility. Disruption of adherens junctions promotes tumor cell invasion and metastasis and is often associated with tumor progression. We detected high levels of RhoA activity in HCA-7 colon carcinoma cells that constitutively express COX-2. Inhibition of COX-2 significantly reduced the levels of RhoA activity in HCA-7 cells, suggesting that constitutive expression of COX-2 stimulates RhoA activity. Interestingly, inhibition of COX-2 or silencing of COX-2 expression with small interfering RNA (siRNA) stimulated the formation of adherens junctions, concomitant with increased protein levels of E-cadherin and alpha-catenin. Furthermore, inhibition of RhoA or silencing of RhoA expression with siRNA increased the levels of L-cadherin and alpha-catenin. Inhibition of Rho kinases (ROCK), the RhoA effector proteins, also increased levels of E-cadherin and alpha-catenin and stimulated formation of adherens junctions. The motility of HCA-7 cells was significantly decreased when COX-2 or RhoA was inhibited. Therefore, our data reveal a novel molecular mechanism that links COX-2 signaling to disrupt the formation of adherens junctions; COX-2 stimulates the RhoA/ROCK pathway, which reduces levels of E-cadherin and alpha-catenin leading to disruption of adherens junction formation and increased motility. Understanding of COX-2 downstream signaling pathways that promote tumor progression is crucial for the development of novel therapeutic strategies.