TY - JOUR
T1 - Roscovitine regulates invasive breast cancer cell (MDA-MB231) proliferation and survival through cell cycle regulatory protein cdk5
AU - Goodyear, Shaun
AU - Sharma, Mahesh C.
N1 - Funding Information:
This study was supported by Department of Defense (DOD) grant DAMD170310761 to MCS.
PY - 2007/2
Y1 - 2007/2
N2 - 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.
AB - 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.
KW - Breast cancer
KW - Cell cycle
KW - Olomoucine
KW - Roscovitine
KW - cdk5/p35
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U2 - 10.1016/j.yexmp.2006.09.002
DO - 10.1016/j.yexmp.2006.09.002
M3 - Article
C2 - 17081516
AN - SCOPUS:33845915536
SN - 0014-4800
VL - 82
SP - 25
EP - 32
JO - Experimental and Molecular Pathology
JF - Experimental and Molecular Pathology
IS - 1
ER -