101. Carbonyl reductase 1 is a new target to improve the effect of radiotherapy on head and neck squamous cell carcinoma
- Author
-
Ji-Youn Sung, Sung-Soo Kim, Miyong Yun, Ae Jin Choi, Munkyoo Kong, Young Chan Lee, and Young-Gyu Eun
- Subjects
Male ,0301 basic medicine ,Cancer Research ,CBR1 ,DNA damage ,medicine.disease_cause ,lcsh:RC254-282 ,Radiation Tolerance ,Radiosensitivity ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Mitotic catastrophe ,Gene knockdown ,Squamous Cell Carcinoma of Head and Neck ,Chemistry ,Research ,Head and neck squamous cell carcinoma ,ROS ,Cell cycle ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Survival Analysis ,Xenograft Model Antitumor Assays ,Head and neck squamous-cell carcinoma ,Gene Expression Regulation, Neoplastic ,Alcohol Oxidoreductases ,Treatment Outcome ,030104 developmental biology ,Oncology ,Head and Neck Neoplasms ,Gene Knockdown Techniques ,030220 oncology & carcinogenesis ,Cancer research ,Ionising radiation ,Reactive Oxygen Species ,Oxidative stress - Abstract
Background Human carbonyl reductase 1 (CBR1) plays major roles in protecting cells against cellular damage resulting from oxidative stress. Although CBR1-mediated detoxification of oxidative materials increased by stressful conditions including hypoxia, neuronal degenerative disorders, and other circumstances generating reactive oxide is well documented, the role of CBR1 under ionising radiation (IR) is still unclear. Methods The formalin-fixed and paraffin-embedded tissues of 85 patients with head and neck squamous cell carcinoma (HNSCC) were used to determine if CBR1 expression effects on survival of patients with treatment of radiotherapy. Subsequently colony formation assays and xenograft tumor mouse model was used to verify the relationship between CBR1 expression and radiosensitivity in HNSCC cells. Publicly-available data from The Cancer Genome Atlas (TCGA) was analysed to determine if CBR1 expression affects the survival of patients with HNSCC. To verify CBR1-mediated molecular signalling pathways, cell survival, DNA damage/repair, reactive oxygen species (ROS), cell cycle distribution and mitotic catastrophe in HNSCC cells with modulated CBR1 expression by knockdown or overexpression were measured using by colony formation assays, flow cytometry, qRT-PCR and western blot analysis. Results HNSCC patients with low CBR1 had a significantly higher survival rate than the high CBR1 expression (84.2% vs. 57.8%, p = 0.0167). Furthermore, HNSCC patients with low CBR1 expression showed a good prognosis for IR compared to patients with highly expressed CBR1. Also, we found that IR upregulated CBR1 mRNA via Nrf2 activation in HNSCC cells and patients. In vitro analysis, we found that CBR1-specific siRNA or inhibitor significantly enhanced radiosensitivity after IR, while CBR1 overexpression decreased. CBR1 inhibition by siRNA or inhibitor treatment accumulated cellular ROS leading to aberrant DNA damage repair and an increase of mitotic catastrophe. Moreover, the combination of CBR1 depletion with IR dramatically inhibited primary tumour growth in a xenograft tumor mouse model. Conclusion Our findings indicate that CBR1 has a key role in DNA damage response through regulation of IR-mediated ROS generation. Consistently, CBR1 expression is highly correlated with patient survival after and susceptibility to radiation therapy. Therefore, CBR1 inhibition with IR might be a potent therapeutic strategy for HNSCC treatment. Electronic supplementary material The online version of this article (10.1186/s13046-018-0942-9) contains supplementary material, which is available to authorized users.
- Published
- 2018