Autophagy suppression enhances DNA damage and cell death upon treatment with PARP inhibitor Niraparib in laryngeal squamous cell carcinoma
Autophagy suppression enhances DNA damage and cell death upon treatment with PARP inhibitor Niraparib in laryngeal squamous cell carcinoma
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DOI：
10.1007/s00253-019-10148-y
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发表时间：
2019-11-04
影响因子：
5
通讯作者：
Ye, Li
中科院分区：
文献类型：
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作者：
Ji, Yunxiang;Wang, Qian;Ye, Li
多聚腺苷二磷酸核糖聚合酶（poly（ADP-ribose）polymerase，PARP）抑制剂作为靶向DNA损伤反应（DNA damage response，DDR）的抗肿瘤药物，已被广泛应用于多种肿瘤的治疗，但其对喉鳞状细胞癌（laryngeal squamous cell carcinoma，LSCC）的作用尚未见报道。在此，我们首次发现PARP-1/2抑制剂Niraparib可同时诱导LSCC TU 212和TU 686细胞的细胞生长抑制和自噬。Niraparib通过阻滞G1期并阻止细胞进入S期来减慢LSCC的细胞周期。Niraparib给药后也观察到DNA损伤，γ H2 AX蓄积和pRB表达减少证明了这一点。此外，通过观察自噬体、LC 3阳性自噬样空泡和LC 3-I向LC 3-II的明显转化证实了自噬的产生。此外，阻断自噬增强了Niraparib诱导的生长抑制和DNA损伤。进一步研究表明，自噬抑制可通过提高蛋白酶体活性来阻断检查点激酶1（Chk 1）的激活，进而损害同源重组（HR）的能力，从而提高Niraparib的抗LSCC效率。总之，这些结果表明，Niraparib和自噬同时靶向可能是临床上LSCC的一种有前景的治疗方案。
Although poly (ADP-ribose) polymerase (PARP) inhibitors, as anti-tumor drugs targeting the DNA damage response (DDR), have been used for the therapy of various tumors, few researches reported their effect on laryngeal squamous cell carcinoma (LSCC). Here, we first discovered that the PARP-1/2 inhibitor Niraparib could simultaneously induce cell growth inhibition and autophagy in LSCC TU212 and TU686 cells. Niraparib decelerated cell cycle of LSCC by arresting G1 phase and preventing the cells from entering S phase. DNA lesions were also observed upon Niraparib treatment as evidenced by the accumulation of gamma H2AX and abatement of pRB expression. In addition, autophagy generation was confirmed by the observation of autophagosomes, LC3-positive autophagy-like vacuoles, and obvious conversion of LC3-I to LC3-II. Moreover, blocking autophagy enhanced Niraparib-induced growth inhibition and DNA lesions. Further studies suggested that autophagy suppression could obstruct the activation of checkpoint kinase 1 (Chk1) through elevating proteasomal activity and then impair the capacity of homologous recombination (HR), thereby improving the anti-LSCC efficiency of Niraparib. Collectively, these findings suggested that simultaneous targeting of Niraparib and autophagy might be a promising therapeutic schedule for LSCC in clinic.