RNA interferences targeting the Fanconi anemia/BRCA pathway upstream genes reverse cisplatin resistance in drug-resistant lung cancer cells.
RNA interferences targeting the Fanconi anemia/BRCA pathway upstream genes reverse cisplatin resistance in drug-resistant lung cancer cells.
复制标题
DOI：
10.1186/s12929-015-0185-4
复制
发表时间：
2015-09-18
影响因子：
11
通讯作者：
Chen YC
中科院分区：
文献类型：
--
作者：
Dai CH;Li J;Chen P;Jiang HG;Wu M;Chen YC
顺铂是肺癌最常用的化疗药物之一。顺铂的治疗效果受到耐药性发展的限制。在这项研究中，我们测试RNA干扰（RNAi）靶向范可尼贫血（FA）/BRCA通路上游基因对顺铂敏感（A549和SK-MES-1）和耐药（A549/DDP）肺癌细胞对顺铂的敏感性的影响。使用小干扰RNA（siRNA），敲低FANCF、FANCL或FANCD 2抑制A549、A549/DDP和SK-MES-1细胞中FA/BRCA通路的功能，并增强这三种细胞对顺铂的敏感性。在A549/DDP细胞中敲除FANCF和/或FANCL后，顺铂诱导的增殖抑制程度显著大于A549和SK-MES-1细胞，表明FANCF和/或FANCL的敲除可以逆转顺铂耐药肺癌细胞对顺铂的耐药性。此外，FANCL基因敲除可提高A549/DDP细胞对顺铂的敏感性和凋亡率，提示FANCL在顺铂诱导的DNA损伤修复中起重要作用。通过RNAi敲低FANCF、FANCL或FANCD 2可协同顺铂通过抑制FA/BRCA通路抑制顺铂耐药肺癌细胞的细胞增殖。
Cisplatin is one of the most commonly used chemotherapy agent for lung cancer. The therapeutic efficacy of cisplatin is limited by the development of resistance. In this study, we test the effect of RNA interference (RNAi) targeting Fanconi anemia (FA)/BRCA pathway upstream genes on the sensitivity of cisplatin-sensitive (A549 and SK-MES-1) and -resistant (A549/DDP) lung cancer cells to cisplatin. Using small interfering RNA (siRNA), knockdown of FANCF, FANCL, or FANCD2 inhibited function of the FA/BRCA pathway in A549, A549/DDP and SK-MES-1 cells, and potentiated sensitivity of the three cells to cisplatin. The extent of proliferation inhibition induced by cisplatin after knockdown of FANCF and/or FANCL in A549/DDP cells was significantly greater than in A549 and SK-MES-1 cells, suggesting that depletion of FANCF and/or FANCL can reverse resistance of cisplatin-resistant lung cancer cells to cisplatin. Furthermore, knockdown of FANCL resulted in higher cisplatin sensitivity and dramatically elevated apoptosis rates compared with knockdown of FANCF in A549/DDP cells, indicating that FANCL play an important role in the repair of cisplatin-induced DNA damage. Knockdown of FANCF, FANCL, or FANCD2 by RNAi could synergize the effect of cisplatin on suppressing cell proliferation in cisplatin-resistant lung cancer cells through inhibition of FA/BRCA pathway.