Modulation of survival pathways in ovarian carcinoma cell lines resistant to platinum compounds
Modulation of survival pathways in ovarian carcinoma cell lines resistant to platinum compounds
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DOI：
10.1158/1535-7163.mct-07-0450
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发表时间：
2008-03-01
影响因子：
5.7
通讯作者：
Zunino, Franco
中科院分区：
文献类型：
--
作者：
Benedetti, Valentina;Perego, Paola;Zunino, Franco
由于细胞毒性应激引发了多种可能与细胞存活或死亡有关的信号通路，它们的改变可能与铂耐药表型的发展有关。因此，在本研究中，我们研究了卵巢癌细胞系对表皮生长因子受体（EGFR）抑制剂吉非替尼的细胞反应，包括对顺铂（IGROV-1/Pt1）和奥沙利铂（IGROV-1/OHP）耐药的细胞。耐药亚系对吉非替尼的敏感性和对细胞凋亡的耐药性显著降低。吉非替尼能够抑制EGFR在所有研究细胞系中的磷酸化。Akt和作用于EGFR下游的细胞外信号调节激酶1/2 （ERK1/2）激酶在三种细胞系中均具有组成性活性，但在两种耐药亚系中磷酸化ERK1/2水平升高。这一特征与MEK1/2抑制剂U0126的敏感性降低有关。用U0126预处理耐药细胞可恢复对吉非替尼的敏感性。吉非替尼抑制IGROV-1细胞ERK1/2和Akt磷酸化的效果优于抑制IGROV-1/OHP和IGROV-1/Pt1细胞。Phospho-p38在耐药亚系中上调，表明不同的丝裂原活化蛋白激酶同时激活。phospho-p38的上调与EGFR的特殊定位有关，而在耐药亚系中，EGFR主要内化。总之，我们的研究结果表明，铂类药物耐药的发展与多种改变有关，包括EGFR激活的生存途径的解除管制，导致细胞对吉非替尼的反应降低。
Because cytotoxic stress elicits various signaling pathways that may be implicated in cell survival or cell death, their alterations may have relevance in the development of platinum-resistant phenotype. Thus, in the present study, we investigated cell response to the epidermal growth factor receptor (EGFR) inhibitor gefitinib of ovarian carcinoma cell lines, including cells selected for resistance to cisplatin (IGROV-1/Pt1) and oxaliplatin (IGROV-1/OHP). Resistant sublines exhibited a marked decrease in sensitivity to gefitinib and resistance to apoptosis. Gefitinib was capable of inhibiting the phosphorylation of EGFR in all the studied cell lines. The Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) kinases, which act downstream of EGFR, were constitutively active in the three cell lines, but phospho-ERK1/2 levels were increased in the two resistant sublines. This feature was associated with reduced sensitivity to the MEK1/2 inhibitor U0126. Pretreatment of resistant cells with U0126 resulted in restoration of sensitivity to gefitinib. Gefitinib was more effective in inhibiting ERK1/2 and Akt phosphorylation in IGROV-1 cells than in IGROV-1/OHP and IGROV-1/Pt1 cells. Phospho-p38 was up-regulated in the resistant sublines, indicating the concomitant activation of distinct mitogen-activated protein kinases. The up-regulation of phospho-p38 was associated with a peculiar localization of EGFR, which, in resistant sublines, was mainly internalized. In conclusion, our results indicate that the development of resistance to platinum drugs is associated with multiple alterations including deregulation of survival pathways activated by EGFR resulting in a reduced cellular response to gefitinib.