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

Cell Death Dis. 2020 Oct 21;11(10):887. doi: 10.1038/s41419-020-03100-w.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autophagy / genetics
  • Autophagy / physiology*
  • DNA Repair
  • DNA-Binding Proteins / metabolism
  • Humans
  • Kelch-Like ECH-Associated Protein 1 / antagonists & inhibitors*
  • Kelch-Like ECH-Associated Protein 1 / metabolism
  • Nuclear Proteins / metabolism
  • Radiation Tolerance / genetics
  • Squamous Cell Carcinoma of Head and Neck / therapy*

Substances

  • DNA-Binding Proteins
  • KEAP1 protein, human
  • Kelch-Like ECH-Associated Protein 1
  • Nuclear Proteins