EGFR-mediated G1/S transition contributes to the multidrug resistance in breast cancer cells
EGFR-mediated G1/S transition contributes to the multidrug resistance in breast cancer cells
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DOI：
10.1007/s11033-011-1347-4
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发表时间：
2012-05-01
影响因子：
2.8
通讯作者：
Wang, Nian-Hong
中科院分区：
文献类型：
--
作者：
Chen, Shu-Jun;Luan, Jing;Wang, Nian-Hong
尽管肿瘤治疗策略不断改进，但多药耐药(MDR)仍是肿瘤治疗成功的关键问题。初次化疗后复发的癌症通常对这些抗癌疗法的第二次治疗是难治的。因此，有必要阐明肿瘤的耐药机制，以开发有效的抗肿瘤治疗方法。在这里，我们展示了一种由表皮生长因子受体(EGFR)引起的人类乳腺癌细胞的时相特异性化疗耐药。胸腺嘧啶核苷诱导的G1期阻滞细胞对化疗药物的敏感性上调，而S期阻滞细胞对化疗药物的耐药性更强。EGFR的过表达通过促进乳腺癌细胞的G1/S期转变而促进其多药耐药表型的形成，而EGFR的缺失则起到相反的作用。此外，与细胞周期有关的蛋白Cyclin D1也参与了EGFR介导的上述效应，因为EGFR上调了Cyclin D1的表达，而针对Cyclin D1的特异性RNA干扰可以主要消除EGFR诱导的MDR表型。这些数据为多药耐药乳腺癌逃避化疗药物的细胞毒攻击的方式提供了新的见解，也表明了EGFR-CylinD1轴在这一过程中的作用。
Despite the improvement of strategies against cancer therapy, the multidrug resistance (MDR)is the critical problem for successful cancer therapy. Recurrent cancers after initial treatment with chemotherapy are generally refractory to second treatments with these anticancer therapies. Therefore, it is necessary to elucidate the therapy-resistant mechanism for development of effective therapeutic modalities against tumors. Here we demonstrate a phase-specific chemotherapy resistance due to epidermal growth factor receptor (EGFR) in human breast cancer cells. Thymidine-induced G1-arrested cultures showed upregulated chemosensitivity, whereas S-phase arrested cells were more resistant to chemotherapeutic agents. Overexpression of EGFR promoted the MDR phenotypes in breast cancer cells via accelerating the G1/S phase transition, whereas depletion of EGFR exerted the opposite effects. Furthermore, CyclinD1, a protein related to cell cycle, was demonstrated to be involved in above EGFR-mediated effects since EGFR increased the expression of CyclinD1, and the specific RNA interference against CyclinD1 could primarily abolish the EGFR-induced MDR phenotypes. These data provide new insights into the mode by which MDR breast cancers evade cytoxic attacks from chemotherapeutic agents and also suggest a role for EGFR-CyclinD1 axis in this process.