Efficacy of poly (ADP-ribose) polymerase inhibitor olaparib against head and neck cancer cells: predictions of drug sensitivity based on PAR–p53–NF-κB interactions

Poly (ADP-ribose) polymerase (PARP) is a key molecule in the DNA damage response (DDR), which is a major target of both chemotherapies and radiotherapies. PARP inhibitors therefore comprise a promising class of anticancer therapeutics. In this study, we evaluated the efficacy of the PARP inhibitor olaparib, and also sought to identify the mechanism and predictive marker associated with olaparib sensitivity in head and neck cancer (HNC) cells. A total of 15 HNC cell lines, including AMC HNC cells, were tested. AMC-HN3 and HN4 exhibited stronger responses to olaparib. Among cisplatin-resistant cell lines, only AMC HN9-cisR cells were significantly suppressed by olaparib. We found that basal poly (ADP-ribose) (PAR) levels, but not PARP-1 levels, correlated with olaparib sensitivity. AMC-HN3 and HN4 cells exhibited higher basal levels of NF-κB that decreased significantly after olaparib treatment. In contrast, apoptotic proteins were intrinsically expressed in AMC-HN9-cisR cells. As interference with p53 expression led to NF-κB reactivation, we concluded that elevated basal PAR and NF-κB levels are predictive of olaparib responsiveness in HNC cells; in addition, olaparib inhibits HNC cells via PAR–p53–NF-κB interactions.

聚(ADP-核糖)聚合酶（Poly (ADP-ribose) polymerase, PARP）是DNA损伤应答（DNA damage response, DDR）中的关键分子，同时亦是化疗与放疗的核心靶标之一。据此，PARP抑制剂已成为一类极具开发前景的抗癌治疗药物。本研究评估了PARP抑制剂奥拉帕利（olaparib）的抗肿瘤活性，并旨在明确头颈部癌（head and neck cancer, HNC）细胞中与奥拉帕利敏感性相关的作用机制与预测生物标志物。本研究共测试了包含AMC HNC细胞在内的15株头颈部癌细胞系。其中，AMC-HN3与HN4细胞对奥拉帕利展现出更显著的应答反应。在顺铂耐药细胞系中，仅AMC HN9-cisR细胞可被奥拉帕利显著抑制增殖。研究发现，基础聚(ADP-核糖)（PAR）水平而非PARP-1蛋白表达水平，与奥拉帕利敏感性呈显著正相关。AMC-HN3与HN4细胞的基础NF-κB水平较高，且经奥拉帕利处理后该水平显著下调。与之相反，AMC-HN9-cisR细胞本就高表达凋亡蛋白。由于干扰p53表达可重新激活NF-κB，本研究得出结论：基础PAR与NF-κB水平升高可预测头颈部癌细胞对奥拉帕利的应答反应；此外，奥拉帕利可通过PAR-p53-NF-κB相互作用通路抑制头颈部癌细胞增殖。