Involvement of Rad51 in cytotoxicity induced by epidermal growth factor receptor inhibitor (gefitinib, IressaR) and chemotherapeutic agents in human lung cancer cells
Involvement of Rad51 in cytotoxicity induced by epidermal growth factor receptor inhibitor (gefitinib, IressaR) and chemotherapeutic agents in human lung cancer cells
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DOI：
10.1093/carcin/bgn130
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发表时间：
2008-07-01
期刊：
影响因子：
4.7
通讯作者：
Lin, Yun-Wei
中科院分区：
文献类型：
--
作者：
Ko, Jen-Chung;Ciou, Shih-Ci;Lin, Yun-Wei
吉非替尼（易瑞沙（R），ZD 1839）是一种选择性表皮生长因子受体（EGFR）酪氨酸激酶抑制剂，可阻断生长因子介导的细胞增殖和细胞外信号调节激酶1/2（ERK 1/2）信号激活。Rad 51是同源重组修复途径的重要组成部分。Rad 51在化疗或放射耐受性癌中的高水平表达已被报道。我们假设吉非替尼可能通过降低ERK 1/2激活和Rad 51表达来增强烷化剂顺铂或抗肿瘤抗生素丝裂霉素C（MMC）介导的细胞毒性的作用。人非小细胞肺癌细胞暴露于吉非替尼降低顺铂或MMC引起的ERK 1/2激活和Rad 51蛋白诱导。顺铂和MMC处理均不影响Rad 51信使RNA（mRNA）。然而，吉非替尼与顺铂或MMC联合治疗显著降低Rad 51 mRNA水平。此外，吉非替尼通过增加Rad 51蛋白的不稳定性降低顺铂或MMC诱导的Rad 51蛋白水平。增强ERK 1/2信号转导的组成型活性丝裂原活化蛋白激酶激酶1/2（MKK 1/2-CA）增加Rad 51蛋白水平和蛋白质稳定性在吉非替尼和顺铂或MMC共处理的细胞。此外，MKK 1-CA介导的ERK 1/2激活增强可显著降低吉非替尼与顺铂或MMC联合诱导的协同细胞毒效应。通过si-Rad 51 RNA转染消除内源性Rad 51表达显著增强了顺铂或MMC治疗后的肺癌细胞死亡。我们的结论是Rad 51蛋白保护肺癌细胞免受吉非替尼和化疗药物诱导的协同细胞毒性作用。Rad 51表达的抑制可能是一种新的肺癌治疗模式，以克服对EGFR抑制剂和化疗药物的耐药性。
Gefitinib (Iressa(R), ZD1839) is a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that blocks growth factor-mediated cell proliferation and extracellular signal-regulated kinases 1/2 (ERK1/2) signaling activation. Rad51 is an essential component of the homologous recombination repair pathway. High level of Rad51 expression has been reported in chemo- or radioresistant carcinomas. We hypothesized that gefitinib may enhance the effects of the alkylating agent cisplatin- or the antitumor antibiotic mitomycin C (MMC)-mediated cytotoxicity by decreasing ERK1/2 activation and Rad51 expression. Exposure of human non-small lung cancer cells to gefitinib decreased cisplatin- or MMC-elicited ERK1/2 activation and Rad51 protein induction. Neither cisplatin nor MMC treatment affected Rad51 messenger RNA (mRNA). However, gefitinib cotreatment with cisplatin or MMC significantly decreased Rad51 mRNA levels. In addition, gefitinib decreased cisplatin- or MMC-elicited Rad51 protein levels by increasing Rad51 protein instability. Enhancement of ERK1/2 signaling by constitutively active mitogen-activated protein kinase kinase 1/2 (MKK1/2-CA) increased Rad51 protein levels and protein stability in gefitinib and cisplatin or MMC cotreated cells. Moreover, the synergistic cytotoxic effects induced by gefitinib cotreatment with cisplatin or MMC were remarkably decreased by MKK1-CA-mediated enhancement of ERK1/2 activation. Depletion of endogenous Rad51 expression by si-Rad51 RNA transfection significantly enhanced lung cancer cell death upon treatment with cisplatin or MMC. We conclude that Rad51 protein protects lung cancer cells from synergistic cytotoxic effects induced by gefitinib and chemotherapeutic agents. Suppression of Rad51 expression may be a novel lung cancer therapeutic modality to overcome drug resistance to EGFR inhibitors and chemotherapeutic agents.