p38 MAPK turns hepatocyte growth factor to a death signal that commits ovarian cancer cells to chemotherapy-induced apoptosis
p38 MAPK turns hepatocyte growth factor to a death signal that commits ovarian cancer cells to chemotherapy-induced apoptosis
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DOI：
10.1002/ijc.21766
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发表时间：
2006-06-15
影响因子：
6.4
通讯作者：
Di Renzo, Maria Flavia
中科院分区：
文献类型：
--
作者：
Coltella, Nadia;Rasola, Andrea;Di Renzo, Maria Flavia
我们最近发现，肝细胞生长因子（HGF），作为一种生存因子，意外地增强了一线化疗药物顺铂（CDDP）和紫杉醇（PTX）治疗的人卵巢癌细胞的凋亡。在这里，我们证明，这种效果取决于p38丝裂原活化激酶（MAPK）。事实上，p38 MAPK活性被HGF刺激，并且通过用HGF和CDDP或PTX的组合处理进一步增加。p38 MAPK的显性负性形式的表达消除了单独或与HGF组合的药物引起的细胞凋亡。HGF和药物还激活ERK 1/2 MAPKs、PI 3 K/AKT和AKT底物mTOR。然而，这些存活途径的激活并不妨碍HGF增强药物依赖性细胞凋亡的能力。总之，数据显示，p38 MAPK是卵巢癌细胞对低剂量CDDP和PTX的HGF敏化所必需的，并且可能足以克服存活途径的激活。因此，p38 MAPK通路可能是一个合适的目标，以改善人类卵巢癌的常规化疗的反应。(c)2006 Wiley-Liss，Inc.
We recently showed that Hepatocyte Growth Factor (HGF), known as a survival factor, unexpectedly enhances apoptosis in human ovarian cancer cells treated with the front-line chemotherapeutics cisplatin (CDDP) and paclitaxel (PTX). Here we demonstrate that this effect depends on the p38 mitogen-activated kinase (MAPK). In fact, p38 MAPK activity is stimulated by HGF and further increased by the combined treatment with HGF and either CDDP or PTX. The expression of a dominant negative form of p38 MAPK abrogates apoptosis elicited by drugs, alone or in combination with HGF. HGF and drugs also activate the ERK1/2 MAPKs, the PI3K/AKT and the AKT substrate mTOR. However, activation of these survival pathways does not hinder the ability of HGF to enhance drug-dependent apoptosis. Altogether data show that p38 MAPK is necessary for HGF sensitization of ovarian cancer cells to low-doses of CDDP and PTX and might be sufficient to overcome activation of survival pathways. Therefore, the p38 MAPK pathway might be a suitable target to improve response to conventional chemotherapy in human ovarian cancer. (c) 2006 Wiley-Liss, Inc.