Research Papers:

PARP-1 inhibitors sensitize HNSCC cells to APR-246 by inactivation of thioredoxin reductase 1 (TrxR1) and promotion of ROS accumulation

Zhi-Xian Yin _, Wei Hang, Gang Liu, Yi-Shu Wang, Xiang-Feng Shen, Qian-Hui Sun, Dong-Dong Li, Yong-Ping Jian, Yang-He Zhang, Cheng-Shi Quan, Qinghua Zeng, Yu-Lin Li, Rui-Xun Zhao, Qiang Ding and Zhi-Xiang Xu

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Oncotarget. 2018; 9:1885-1897. https://doi.org/10.18632/oncotarget.21277

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Zhi-Xian Yin1,*, Wei Hang1,3,*, Gang Liu1, Yi-Shu Wang2, Xiang-Feng Shen2, Qian-Hui Sun2, Dong-Dong Li2, Yong-Ping Jian2, Yang-He Zhang2, Cheng-Shi Quan2, Qinghua Zeng2,3, Yu-Lin Li2, Rui-Xun Zhao3, Qiang Ding4 and Zhi-Xiang Xu2,3

1Department of Otorhinolaryngology Head and Neck Surgery, Tianjin Huanhu Hospital, Tianjin, China

2Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, China

3Division of Hematology and Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, USA

4Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA

*These authors have contributed equally to this work

Correspondence to:

Zhi-Xian Yin, email: [email protected]

Zhi-Xiang Xu, email: [email protected]

Keywords: head and neck squamous cell carcinoma (HNSCC); PARP-1 inhibitors; p53 reactivators; reactive oxygen species (ROS); thioredoxin reductase 1 (TrxR1)

Received: May 11, 2017    Accepted: August 26, 2017    Published: September 26, 2017


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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