Keap1 inhibition sensitizes head and neck squamous cell carcinoma cells to ionizing radiation via impaired non-homologous end joining and induced autophagy

被引：14
|
作者：
Deville, Sara Sofia [1 ,2 ,3 ]
Luft, Susanne [1 ,2 ]
Kaufmann, Maria [1 ,2 ]
Cordes, Nils [1 ,2 ,3 ,4 ,5 ,6 ]
机构：
[1] Tech Univ Dresden, OncoRay Natl Ctr Radiat Res Oncol, Fac Med, Dresden, Germany
[2] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Dresden, Germany
[3] Helmholtz Zentrum Dresden Rossendorf, Inst Radiooncol OncoRay, Dresden, Germany
[4] Tech Univ Dresden, Fac Med, Dept Radiotherapy & Radiat Oncol, Dresden, Germany
[5] German Canc Consortium DKTK, Partner Site Dresden, Dresden, Germany
[6] German Canc Res Ctr, Heidelberg, Germany
来源：
CELL DEATH & DISEASE | 2020年 / 11卷 / 10期
基金：
欧盟地平线“2020”;
关键词：
DNA-DAMAGE RESPONSE; REPAIR; CANCER; PATHWAY; DEFICIENCY; CROSSTALK; CONFERS; TARGET;
D O I：
10.1038/s41419-020-03100-w
中图分类号：
Q2 [细胞生物学];
学科分类号：
071009 ; 090102 ;
摘要：
The function of Keap1 (Kelch-like ECH-associated protein 1), a sensor of oxidative and electrophilic stress, in the radiosensitivity of cancer cells remains elusive. Here, we investigated the effects of pharmacological inhibition of Keap1 with ML344 on radiosensitivity, DNA double-strand break (DSB) repair and autophagy in head and neck squamous cell carcinoma (HNSCC) cell lines. Our data demonstrate that Keap1 inhibition enhances HNSCC cell radiosensitivity. Despite elevated, Nrf2-dependent activity of non-homologous end joining (NHEJ)-related DNA repair, Keap1 inhibition seems to impair DSB repair through delayed phosphorylation of DNA-PKcs. Moreover, Keap1 inhibition elicited autophagy and increased p62 levels when combined with X-ray irradiation. Our findings suggest HNSCC cell radiosensitivity, NHEJ-mediated DSB repair, and autophagy to be co-regulated by Keap1.
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页数：13
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