Cdc6 contributes to cisplatin-resistance by activation of ATR-Chk1 pathway in bladder cancer cells

Oncotarget. 2016 Jun 28;7(26):40362-40376. doi: 10.18632/oncotarget.9616.

Abstract

High activation of DNA damage response is implicated in cisplatin (CDDP) resistance which presents as a serious obstacle for bladder cancer treatment. Cdc6 plays an important role in the malignant progression of tumor. Here, we reported that Cdc6 expression is up-regulated in bladder cancer tissues and is positively correlated to high tumor grade. Cdc6 depletion can attenuate the malignant properties of bladder cancer cells, including DNA replication, migration and invasion. Furthermore, higher levels of chromatin-binding Cdc6 and ATR were detected in CDDP-resistant bladder cancer cells than in the parent bladder cancer cells. Intriguingly, down-regulation of Cdc6 can enhance sensitivity to CDDP both in bladder cancer cells and CDDP-resistant bladder cancer cells. Cdc6 depletion abrogates S phase arrest caused by CDDP, leading to aberrant mitosis by inactivating ATR-Chk1-Cdc25C pathway. Our results indicate that Cdc6 may be a promising target for overcoming CDDP resistance in bladder cancer.

Keywords: ATR; Cdc6; bladder cancer; cisplatin-resistance.

MeSH terms

  • Apoptosis
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • Cell Cycle Proteins / metabolism*
  • Cell Line, Tumor
  • Cell Survival
  • Checkpoint Kinase 1 / metabolism*
  • Chromatin / chemistry
  • Cisplatin / chemistry
  • DNA Damage
  • DNA Replication
  • Disease Progression
  • Down-Regulation
  • Drug Resistance, Neoplasm / drug effects
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Mitosis
  • Nuclear Proteins / metabolism*
  • RNA, Small Interfering / metabolism
  • Urinary Bladder Neoplasms / drug therapy
  • Urinary Bladder Neoplasms / metabolism*
  • cdc25 Phosphatases / metabolism

Substances

  • CDC6 protein, human
  • Cell Cycle Proteins
  • Chromatin
  • Nuclear Proteins
  • RNA, Small Interfering
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • CDC25C protein, human
  • cdc25 Phosphatases
  • Cisplatin