Pharmacological inhibition of cyclin dependent kinases causes p53 dependent apoptosis in renal cell carcinoma.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 20850841.
- Also identified by DOI 10.1016/j.juro.2010.06.088.
- No licence information is recorded for this record.
- Because redistribution is not established, this page shows the abstract only. Follow the links below for the full text.
Abstract
PURPOSE: We evaluated the effect of roscovitine (Sigma-Aldrich®), a pharmacological inhibitor of cyclin dependent kinase, on renal cell carcinoma cell lines in vitro. MATERIALS AND METHODS: We exposed several renal cell carcinoma cell lines to roscovitine and examined apoptotic signaling pathways using immunoblotting and immunohistochemistry. RESULTS: As expected, roscovitine caused dose and time dependent inhibition of cyclin dependent kinase 2 autophosphorylation, and of cyclin dependent kinase mediated Pol II phosphorylation in the ACHN (p53-wt) and 786-O (p53 inactive) renal cell carcinoma cell lines (ATCC®). Roscovitine also induced apoptosis in each cell line within a narrow concentration range (about 10 μg/ml). Apoptosis induction was more efficient in ACHN than in 786-O cells and at least partly due to p53 activity. In ACHN cells roscovitine induced apoptosis was associated with p21 induction, and decreased Akt1, XIAP and phospho-Rb expression. These changes also depended on p53 and were not present (p21) or showed a different dose pattern (Akt1, XIAP and phospho-Rb) in 786-O cells. Partial restoration of roscovitine induced apoptosis in 786-O cells by the Mdm-2 inhibitor nutlin-3 (Sigma-Aldrich) suggests that the inactivating mutation of VHL in these cells and its destabilizing effect on p53 are responsible for the decreased sensitivity to apoptosis. CONCLUSIONS: Our data extend previous studies documenting the pro-apoptotic effect of roscovitine and to our knowledge show for the first time that this activity is restricted to a narrow dose range in renal cell carcinoma cells and partly depends on p53. Thus, roscovitine is a novel potential chemotherapy in a subset of patients with renal cell carcinoma if a narrow therapeutic window is used. These data also provide insight into the role of VHL mutation and p53 in the renal cell carcinoma response to therapeutic cyclin dependent kinase manipulation.