Roscovitine regulates invasive breast cancer cell (MDA-MB231) proliferation and survival through cell cycle regulatory protein cdk5

Shaun Goodyear, Mahesh C. Sharma

Research output: Contribution to journalArticlepeer-review

70 Scopus citations

Abstract

Roscovitine, a purine analogue, has been considered for the treatment of cancer. Anti-cancer therapeutic efficacy is being evaluated in clinical trials. However, the mechanisms remain unclear. In the present study, cyclic-dependent kinase 5 (cdk5) proved to be a molecular target for roscovitine-triggered apoptosis for highly invasive breast cancer cell death. Because our previous studies have shown a potential role of cdk5 in endothelial cell proliferation/apoptosis [Sharma, M.R., Tuszynski, G.P., Sharma, M.C. (2004). Angiostatin-induced inhibition of endothelial cell proliferation/apoptosis is associated with the down-regulation of cell cycle regulatory protein cdk5. J. Cell Biochem. 91, 398-409], here we not only demonstrate first that Cdk5, p35, and p25 proteins were all expressed in invasive breast cancer cells MDA-MB231 but also showed that cdk5 expression regulates MDA-MB231 cell proliferation. In addition, potent mitogen bFGF up-regulates cdk5 expression. Roscovitine specifically inhibits cdk5 expression/activity in a dose-dependent manner with concomitant inhibition of MDA-MB231 cell proliferation and induction of apoptosis. By contrast, the roscovitine analog olomoucine, a specific inhibitor of cdk4, failed to affect MDA-MB231 cell proliferation and apoptosis which implies the specific involvement of cdk5 in roscovitine-triggered cell death/proliferation. Additionally, roscovitine-mediated inhibition of proliferation is irreversible. These data suggest that cdk5 may have a significant role in the regulation of breast cancer cell proliferation and apoptosis and extend beyond its role in neurogenesis. These results suggest that Cdk5 is a novel player in roscovitine-triggered breast cancer cell apoptosis and inhibition of proliferation, therefore, may be a potential therapeutic target.

Original languageEnglish (US)
Pages (from-to)25-32
Number of pages8
JournalExperimental and Molecular Pathology
Volume82
Issue number1
DOIs
StatePublished - Feb 2007
Externally publishedYes

Keywords

  • Breast cancer
  • cdk5/p35
  • Cell cycle
  • Olomoucine
  • Roscovitine

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Clinical Biochemistry

Fingerprint Dive into the research topics of 'Roscovitine regulates invasive breast cancer cell (MDA-MB231) proliferation and survival through cell cycle regulatory protein cdk5'. Together they form a unique fingerprint.

Cite this