Abstract
BackgroundCisplatin 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.ResultUsing 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.ConclusionKnockdown 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.
Highlights
Cisplatin is one of the most commonly used chemotherapy agent for lung cancer
Knockdown of FANCF, FANCL, or FANCD2 by RNA interference (RNAi) could synergize the effect of cisplatin on suppressing cell proliferation in cisplatin-resistant lung cancer cells through inhibition of Fanconi anemia (FA)/BRCA pathway
The results showed that the levels of FANCD2 monoubiquitination induced by cisplatin in A549/DDP cells, as indicated by the ratio of FANCD2-L to FANCD2-S, were much higher than those in A549 cells (Fig. 1b-d)
Summary
Cisplatin is one of the most commonly used chemotherapy agent for lung cancer. A DNA cross-linking agent, is one of the most commonly used drugs in the treatment of lung cancer, including non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) [1, 2]. Cisplatin-based chemotherapy is used as the standard treatment for patients with advanced NSCLC and SCLC, patients respond to the therapy had been more variable, and essentially all patients relapse due to acquired drug resistance [3, 4]. A great understanding of mechanisms of cisplatin resistance are essential to provide a strategy for sensitizing some drug-resistant tumor cells and improve treatment of patients with lung cancer. It is ordinarily thought that the intrastrand cross-links may be the major type of DNA lesions responsible for the toxic effects of cisplatin.
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