PARP-1 inhibitors sensitize HNSCC cells to APR-246 by inactivation of thioredoxin reductase 1 (TrxR1) and promotion of ROS accumulation.
PARP-1 inhibitors sensitize HNSCC cells to APR-246 by inactivation of thioredoxin reductase 1 (TrxR1) and promotion of ROS accumulation.
复制标题
PARP-1 抑制剂通过灭活硫氧还蛋白还原酶 1 (TrxR1) 并促进 ROS 积累使 HNSCC 细胞对 APR-246 敏感
DOI：
10.18632/oncotarget.21277
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发表时间：
2018-01-05
期刊：
影响因子：
--
通讯作者：
Xu ZX
中科院分区：
文献类型：
--
作者：
Yin ZX;Hang W;Liu G;Wang YS;Shen XF;Sun QH;Li DD;Jian YP;Zhang YH;Quan CS;Zeng Q;Li YL;Zhao RX;Ding Q;Xu ZX
头颈鳞状细胞癌（HNSCC）是全球第六大常见癌症。在未感染人乳头瘤病毒（HPV）的 HNSCC 患者中，TP53 突变可能达到 70% - 85%。尽管患者在治疗早期对手术、放疗和化疗有反应，但 TP53 基因突变的 HNSCC 患者的复发率仍然特别高。 p53-重新激活和诱导大量细胞凋亡-1 (PRIMA-1) 及其甲基化类似物 PRIMA-1Met（也称为 APR-246）是奎宁环化合物，可挽救突变型 p53 (mut-p53) 的 DNA 结合活性并恢复野生型 p53 的潜力。在本报告中，我们证明用 6(5H)-菲啶酮 (PHEN) 和 N-(6-Oxo-5,6-二氢菲啶-2-基)-(N,N-二甲基氨基)乙酰胺盐酸盐 (PJ34) 抑制聚 (ADP-核糖) 聚合酶-1 (PARP-1) 可使 UMSCC1、UMSCC14 和 UMSCC14 敏感。 UMSCC17A、APR-246 治疗的三种 HNSCC 细胞系。 PHEN 增强 APR-246 诱导的细胞凋亡，但不增强 HNSCC 细胞的程序性坏死或自噬性细胞死亡。 PARP-1 抑制诱导的 HNSCC 细胞对 APR-246 的敏感性与 TP53 突变无关。相反，PARP-1 抑制会促进 APR-246 促进的硫氧还蛋白还原酶 1 (TrxR1) 失活，导致 ROS 积累和 DNA 损伤。在 HNSCC 细胞中，TrxR1 的过表达或抗氧化剂 N-乙酰基-L-半胱氨酸 (NAC) 的应用会消耗 ROS 的增加，减少 DNA 损伤，并减少 APR-246/PHEN 引发的细胞死亡。因此，我们通过灭活TrxR1和升高ROS来表征PARP-1抑制剂在HNSCC细胞中的新功能，并通过PARP-1抑制剂和APR-246的组合为HNSCC提供新的治疗策略。
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Mutations of TP53 may reach 70% - 85% in HNSCC patients without human papillomavirus (HPV) infection. Recurrence rate remains particularly high for HNSCC patients with mutations in the TP53 gene although patients are responsive to surgery, irradiation, and chemotherapy early in the treatment. p53-Reactivation and Induction of Massive Apoptosis-1 (PRIMA-1) and its methylated analogue PRIMA-1Met (also known as APR-246) are quinuclidine compounds that rescue the DNA-binding activity of mutant p53 (mut-p53) and restore the potential of wild-type p53. In the current report, we demonstrated that inhibition of poly (ADP-ribose) polymerase-1 (PARP-1) with 6(5H)-phenanthridinone (PHEN) and N-(6-Oxo-5,6-dihydrophenanthridin-2-yl)-(N, N-dimethylamino) acetamide hydrochloride (PJ34) sensitizes UMSCC1, UMSCC14, and UMSCC17A, three HNSCC cell lines to the treatment of APR-246. PHEN enhances APR-246-induced apoptosis, but not programmed necrosis or autophagic cell death in HNSCC cells. The PARP-1 inhibition-induced sensitization of HNSCC cells to APR-246 is independent of TP53 mutation. Instead, PARP-1 inhibition promotes APR-246-facilitated inactivation of thioredoxin reductase 1 (TrxR1), leading to ROS accumulation and DNA damage. Overexpression of TrxR1 or application of antioxidant N-acetyl-L-cysteine (NAC) depletes the ROS increase, reduces DNA damage, and decreases cell death triggered by APR-246/PHEN in HNSCC cells. Thus, we have characterized a new function of PARP-1 inhibitor in HNSCC cells by inactivation of TrxR1 and elevation of ROS and provide a novel therapeutic strategy for HNSCC by the combination of PARP-1 inhibitors and APR-246.
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影响因子：
28.2
作者：
Iglesias-Bartolome R;Martin D;Gutkind JS
通讯作者：
Gutkind JS
影响因子：
4.8
作者：
Anestål, K;Arnér, ESJ
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影响因子：
64.8
作者：
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影响因子：
8
作者：
Lambert, J. M. R.;Moshfegh, A.;Bykov, V. J. N.
通讯作者：
Bykov, V. J. N.
影响因子：
11.2
作者：
Leroy B;Ballinger ML;Baran-Marszak F;Bond GL;Braithwaite A;Concin N;Donehower LA;El-Deiry WS;Fenaux P;Gaidano G;Langerød A;Hellstrom-Lindberg E;Iggo R;Lehmann-Che J;Mai PL;Malkin D;Moll UM;Myers JN;Nichols KE;Pospisilova S;Ashton-Prolla P;Rossi D;Savage SA;Strong LC;Tonin PN;Zeillinger R;Zenz T;Fraumeni JF Jr;Taschner PE;Hainaut P;Soussi T
通讯作者：
Soussi T