Circadian clock protein CRY1 prevents paclitaxel‑induced senescence of bladder cancer cells by promoting p53 degradation

Oncol Rep. 2021 Mar;45(3):1033-1043. doi: 10.3892/or.2020.7914. Epub 2020 Dec 30.

Abstract

Bladder cancer is a common tumor type of the urinary system, which has high levels of morbidity and mortality. The first‑line treatment is cisplatin‑based combination chemotherapy, but a significant proportion of patients relapse due to the development of drug resistance. Therapy‑induced senescence can act as a 'back‑up' response to chemotherapy in cancer types that are resistant to apoptosis‑based anticancer therapies. The circadian clock serves an important role in drug resistance and cellular senescence. The aim of the present study was to investigate the regulatory effect of the circadian clock on paclitaxel (PTX)‑induced senescence in cisplatin‑resistant bladder cancer cells. Cisplatin‑resistant bladder cancer cells were established via long‑term cisplatin incubation. PTX induced apparent senescence in bladder cancer cells as demonstrated via SA‑β‑Gal staining, but this was not observed in the cisplatin‑resistant cells. The cisplatin‑resistant cells entered into a quiescent state with prolonged circadian rhythm under acute PTX stress. It was identified that the circadian protein cryptochrome1 (CRY1) accumulated in these quiescent cisplatin‑resistant cells, and that CRY1 knockdown restored PTX‑induced senescence. Mechanistically, CRY1 promoted p53 degradation via increasing the binding of p53 with its ubiquitin E3 ligase MDM2 proto‑oncogene. These data suggested that the accumulated CRY1 in cisplatin‑resistant cells could prevent PTX‑induced senescence by promoting p53 degradation.

Keywords: circadian rhythm; cryptochrome 1; paclitaxel-induced senescence; p53.

MeSH terms

  • Cell Line, Tumor
  • Cellular Senescence / drug effects*
  • Circadian Clocks / genetics
  • Circadian Rhythm / drug effects
  • Circadian Rhythm / genetics
  • Cisplatin / pharmacology
  • Cryptochromes / genetics
  • Cryptochromes / metabolism*
  • Drug Resistance, Neoplasm / drug effects
  • Humans
  • Paclitaxel / pharmacology*
  • Proteolysis
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Tumor Suppressor Protein p53 / metabolism*
  • Ubiquitination
  • Urinary Bladder Neoplasms / metabolism
  • Urinary Bladder Neoplasms / pathology*

Substances

  • CRY1 protein, human
  • Cryptochromes
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • Paclitaxel
  • Cisplatin

Grant support

This work was supported by the grants from the Shenzhen Science and Technology Project (grant nos. JCYJ20180305164655077 and JCYJ20180305124227251) and the National Natural Science Foundation of China (grant no. 81672915).