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Cited by 19PARP inhibition in cancer therapyRedox biology and oxidative stressHead and Neck Cancer Studies

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

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Yin, Zhi-Xian, Hang, Wei, Liu, Gang, Wang, Yi-Shu, Shen, Xiang-Feng, Sun, Qian-Hui, Li, Dong-Dong, Jian, Yong-Ping +7 more·2018·Oncotarget
DOI 10.18632/oncotarget.21277PMC PMC5788606
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Abstract

// Zhi-Xian Yin 1, * , Wei Hang 1, 3, * , Gang Liu 1 , Yi-Shu Wang 2 , Xiang-Feng Shen 2 , Qian-Hui Sun 2 , Dong-Dong Li 2 , Yong-Ping Jian 2 , Yang-He Zhang 2 , Cheng-Shi Quan 2 , Qinghua Zeng 2, 3 , Yu-Lin Li 2 , Rui-Xun Zhao 3 , Qiang Ding 4 and Zhi-Xiang Xu 2, 3 1 Department of Otorhinolaryngology Head and Neck Surgery, Tianjin Huanhu Hospital, Tianjin, China 2 Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, China 3 Division of Hematology and Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, USA 4 Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA * These authors have contributed equally to this work Correspondence to: Zhi-Xian Yin, email: yinzhixian74@sohu.com Zhi-Xiang Xu, email: zhixiangxu08@gmail.com 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 ABSTRACT 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-1 Met (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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Authors
Yin, Z.-X., Hang, W., Liu, G., Wang, Y.-S., Shen, X.-F., Sun, Q.-H., Li, D.-D., Jian, Y.-P., Zhang, Y.-H., Quan, C.-S., Zeng, Q., Li, Y.-L., Zhao, R.-X., Ding, Q., & Xu, Z.-X.
Affiliations
  • Tianjin Huanhu Hospital (CN)
  • University of Alabama at Birmingham (US)
  • Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, China
  • Jilin University (CN)
Corresponding author
  • Yin, Zhi-Xian
  • Hang, Wei
ORCID
Venue
Oncotarget
Publisher
Impact Journals, LLC
Published
2017-09-26
Volume
9
Issue
2
Pages
1885-1897
ISSN
1949-2553 (ISSN-L)
DOI
10.18632/oncotarget.21277
PMC
PMC5788606
OpenAlex
W2758909285
Cited by
19
References
3
Citations by year
2026: 1 · 2024: 2 · 2023: 1 · 2022: 3 · 2021: 4 · 2020: 1 · 2019: 5 · 2018: 2
FWCI
0.96
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Oncotarget (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Natural Science Foundation of China (81772924, 81271853, 81573087, 81272243)
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (R01HL085324, R01HL127338)
  • National Cancer Institute (R01CA133053)
Topics
  • Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Health Sciences › Medicine › Otorhinolaryngology › Head and Neck Cancer Studies
Keywords
PARP-1 inhibitors, APR-246, PRIMA-1, thioredoxin reductase 1, reactive oxygen species, head and neck squamous cell carcinoma, TP53 mutation, mutant p53 reactivation, drug synergy, radiosensitization, apoptosis, oxidative stress, combination therapy, chemosensitization

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