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Experimental Therapeutics, Molecular Targets, and Chemical Biology |
Departments of 1 Experimental Radiation Oncology and 2 Surgical Oncology, M.D. Anderson Cancer Center, Houston, Texas
Requests for reprints: Khandan Keyomarsi, Experimental Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 66, Houston, TX 77030-4095. Phone: 713-792-4845; Fax: 713-794-5369; E-mail: kkeyomar{at}mdanderson.org.
Previously, we reported that breast cancer cells with retinoblastoma (pRb) pathwaydefective checkpoints can be specifically targeted with chemotherapeutic agents, following staurosporine-mediated reversible growth inhibition in normal cells. Here we set out to determine if the kinetics of staurosporine-mediated growth inhibition is specifically targeted to the G1 phase of cells, and if such G1 arrest requires the activity of wild-type pRb. Normal human mammary epithelial and immortalized cells with intact pRb treated with low concentrations of staurosporine arrested in the G1 phase of the cell cycle, whereas pRb-defective cells showed no response. The duration of G1 and transition from G1 to S phase entry were modulated by staurosporine in Rb-intact cells. In pRb+ cells, but not in Rb cells, low concentrations of staurosporine also resulted in a significant decrease in cyclin-dependent kinase 4 (CDK4) expression and activity. To directly assess the role of pRb in staurosporine-mediated G1 arrest, we subjected wild-type (Rb+/+) and pRb/ mouse embryo fibroblasts (MEFs) to staurosporine treatments. Our results show that whereas Rb+/+ MEFs were particularly sensitive to G1 arrest mediated by staurosporine, pRb/ cells were refractory to such treatment. Additionally, CDK4 expression was also inhibited in response to staurosporine only in Rb+/+ MEFs. These results were recapitulated in breast cancer cells treated with siRNA to pRb to down-regulate the pRb expression. Collectively, our data suggest that treatment of cells with nanomolar concentrations of staurosporine resulted in down-regulation of CDK4, which ultimately leads to G1 arrest in normal human mammary epithelial and immortalized cells with an intact pRb pathway, but not in pRb-null/defective cells. (Cancer Res 2006; 66(19): 9744-53)
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N. Bandi, S. Zbinden, M. Gugger, M. Arnold, V. Kocher, L. Hasan, A. Kappeler, T. Brunner, and E. Vassella miR-15a and miR-16 Are Implicated in Cell Cycle Regulation in a Rb-Dependent Manner and Are Frequently Deleted or Down-regulated in Non-Small Cell Lung Cancer Cancer Res., July 1, 2009; 69(13): 5553 - 5559. [Abstract] [Full Text] [PDF] |
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