Targeting Epidermal Growth Factor Receptor-Associated Signaling Pathways in Non-Small Cell Lung Cancer Cells: Implication in Radiation Response
Targeting Epidermal Growth Factor Receptor-Associated Signaling Pathways in Non-Small Cell Lung Cancer Cells: Implication in Radiation Response
复制标题
DOI：
10.1158/1541-7786.mcr-09-0507
复制
发表时间：
2010-07-01
影响因子：
5.2
通讯作者：
Kim, In Ah
中科院分区：
文献类型：
--
作者：
Choi, Eun Jung;Ryu, Yun Kyeong;Kim, In Ah
一些研究表明，靶向表皮生长因子受体(EGFR)信号转导信号增强辐射抗肿瘤活性的潜在价值。然而，治疗耐药已成为一个重要的临床问题。在这里，我们调查了靶向EGFR相关下游信号的策略是否会使一组非小细胞肺癌细胞系变得对辐射敏感。用RNA干扰抑制K-RAS可减弱A549和H460细胞的下游信号转导，提高其放射敏感性，而抑制EGFR则无此作用。在密码子V12处存在K-RAS突变的A549细胞被针对该密码子的小干扰RNA(SiRNA)放射增敏。具有V61密码子突变的H460细胞可通过靶向该突变的siRNA进行放射增敏。K-RAS siRNA对野生型K-RAS的H1299细胞不具有放射增敏作用。抑制磷脂酰肌醇3-激酶(PI3K)-AKT-雷帕霉素途径的哺乳动物靶标导致这两种细胞系具有显著的放射增敏作用，而选择性抑制细胞外信号调节的激酶信号转导不能。靶向PI3K-AKT-mTOR通路的抑制剂也可抑制照射后G(2)期的停滞，并诱导γ-H_2AX焦点的形成。I类PI3K的双重抑制剂和哺乳动物靶标雷帕霉素有效地增加了A549和H460细胞的放射敏感性。PI3K-AKT信号的抑制与DNA-PKs的下调有关。当LY294002或AKT抑制剂VIII处理细胞时，细胞死亡以细胞凋亡为主，而雷帕霉素或PI-103处理细胞后，细胞死亡呈现多种模式，包括细胞凋亡和自噬。我们的结果提示了对抗EGFR生存信号与辐射抗性有关的可能机制，并为克服与辐射联合使用的EGFR抑制剂的耐药性提供了一种替代策略。摩尔癌症资源；8(7)；1027-36。(C)2010年AACR。
Several studies have shown solid evidence for the potential value of targeting epidermal growth factor receptor (EGFR) signaling to enhance the antitumor activity of radiation. However, therapeutic resistance has emerged as an important clinical issue. Here, we investigated whether strategies for targeting EGFR-associated downstream signaling would radiosensitize a panel of non-small cell lung cancer cell lines. Inhibition of K-RAS using RNA interference attenuated downstream signaling and increased radiosensitivity of A549 and H460 cells, whereas inhibition of EGFR did not. A549 cells harboring a K-RAS mutation at codon V12 were radiosensitized by small interfering RNA (siRNA) targeting this codon. H460 cells having mutation at codon V61 was radiosensitized by siRNA targeting of this mutation. K-RAS siRNA did not radiosensitize H1299 cells possessing wild-type K-RAS. Inhibition of the phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin pathway led to significant radiosensitization of the two cell lines, whereas selective inhibition of extracellular signal-regulated kinase signaling did not. Inhibitors targeting the PI3K-AKT-mTOR pathway also abrogated G(2) arrest following irradiation and induced gamma H2AX foci formation. A dual inhibitor of class I PI3K and mammalian target of rapamycin effectively increased the radiosensitivity of A549 and H460 cells. Inhibition of PI3K-AKT signaling was associated with the downregulation of DNA-PKs. Although apoptosis was the primary mode of cell death when cells were pretreated with LY294002 or AKT inhibitor VIII, cells pretreated with rapamycin or PI-103 showed mixed modes of cell death, including apoptosis and autophagy. Our results suggest possible mechanisms for counteracting EGFR prosurvival signaling implicated in radioresistance and offer an alternative strategy for overcoming resistance to EGFR inhibitors used in combination with irradiation. Mol Cancer Res; 8(7); 1027-36. (C) 2010 AACR.