Staurosporine-induced G(1) arrest in cancer cells depends on an intact pRB but is independent of p16 status.
Staurosporine and its derivative 7-hydroxystaurosporine are protein kinase inhibitors that are being considered for treatments of cancers. Several recent studies have shown that cells with defective pRB protein are resistant to the G(1) cell cycle-inhibiting effects of staurosporine compounds. In this study, we examined the effect of staurosporine on two breast cancer-derived and three lung cancer-derived cell lines characterized by deficiencies in the p16 tumor suppressor. All of these p16-deficient cell lines are highly sensitive to staurosporine-induced inhibition of pRB phosphorylation and induction of arrest in G(1). This response is similar to that seen in cultured normal human bronchial epithelial cells and normal mammary epithelial cells, but strikingly different than the staurosporine resistance seen in cancer cells with defective pRB. Interestingly, inhibition of pRB phosphorylation could be seen within 4 h of treatment, suggesting that this inhibition is a consequence of direct effects of staurosporine on protein kinase(s) rather than a result of induction of other cyclin-dependent kinase inhibitors. Our findings suggest that different types of cancer cells have vastly different responses to the staurosporine class of agents, and that evaluation of pRB and p16 will help predict the response of the cancer cells to these agents.
Zhou
Weibo
W
Department of Pathology, Johns Hopkins University School of Medicine, 418 No. Bond Street, Baltimore, MD 21231, USA.
Lin
Yuan
Y
Wersto
Robert
R
Chrest
Joseph
J
Gabrielson
Edward
E
D000230:Adenocarcinoma; D001943:Breast Neoplasms; D002460:Cell Line; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D004261:DNA Replication / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D016193:G1 Phase / Q000187:drug effects*; D006801:Humans; D007700:Kinetics; D008175:Lung Neoplasms; D016160:Retinoblastoma Protein / Q000187:drug effects / Q000378:metabolism*; D019311:Staurosporine / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D019941:Cyclin-Dependent Kinase Inhibitor p16; D004791:Enzyme Inhibitors; D016160:Retinoblastoma Protein; D019311:Staurosporine