Lysophosphatidic acid prevents apoptosis of Caco-2 colon cancer cells via activation of mitogen-activated protein kinase and phosphorylation of Bad
Lysophosphatidic acid prevents apoptosis of Caco-2 colon cancer cells via activation of mitogen-activated protein kinase and phosphorylation of Bad
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DOI：
10.1016/j.bbagen.2007.04.008
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发表时间：
2007-08-01
影响因子：
3
通讯作者：
Yun, C. Chris
中科院分区：
文献类型：
--
作者：
Rusovici, Raluca;Ghaleb, Amr;Yun, C. Chris
溶血磷脂酸（LPA）通过特异性G蛋白偶联受体发挥生长因子样作用。不同LPA受体的存在通常决定了LPA在不同环境中的特定信号传导机制和生理后果。在LPA受体家族的四个成员中，LPA（2）已被证明在结肠癌中过表达，这表明LPA（2）的信号传导可能增强肿瘤细胞的生长和存活。在这项研究中，我们使用Caco-2细胞作为细胞模型系统，研究了LPA对结肠癌细胞存活的影响。LPA拯救了化疗药物依托泊苷诱导的Caco-2细胞凋亡。这种保护伴随着废除依托泊苷诱导的半胱天冬酶活性的刺激通过依赖于Erk和PI 3 K的机制。相反，通过敲低支架蛋白NHERF 2而干扰LPA 2受体介导的细胞信号传导，消除了LPA的保护作用。足叶乙甙可降低Bcl-2的表达，LPA可逆转该作用。依托泊苷以ERK依赖的方式降低促凋亡蛋白Bad的磷酸化水平，而不改变Bad的表达。我们进一步表明，LPA治疗导致延迟激活的ERK。这些结果表明，LPA通过涉及Erk、Bad和Bcl-2的机制保护Caco-2细胞免受凋亡损伤。(C)2007 Elsevier B. V.保留所有权利。
Lysophosphatidic acids (LPA) exert growth factor-like effects through specific G protein-coupled receptors. The presence of different LPA receptors often determines the specific signaling mechanisms and the physiological consequences of LPA in different environments. Among the four members of the LPA receptor family, LPA(2) has been shown to be overexpressed in colon cancer suggesting that the signaling by LPA(2) may potentiate growth and survival of tumor cells. In this study, we examined the effect of LPA on survival of colon cancer cells using Caco-2 cells as a cell model system. LPA rescued Caco-2 cells from apoptosis elicited by the chemotherapeutic drug, etoposide. This protection was accompanied by abrogation of etoposide-induced stimulation of caspase activity via a mechanism dependent on Erk and PI3K. In contrast, perturbation of cellular signaling mediated by the LPA2 receptor by knockdown of a scaffold protein NHERF2 abrogated the protective effect of LPA. Etoposide decreased the expression of Bcl-2, which was reversed by LPA. Etoposide decreased the phosphorylation level of the proapoptotic protein Bad in an Erk-dependent manner, without changing Bad expression. We further show that LPA treatment resulted in delayed activation of Erk. These results indicate that LPA protects Caco-2 cells from apoptotic insult by a mechanism involving Erk, Bad, and Bcl-2. (C) 2007 Elsevier B.V. All rights reserved.