PKCalpha/beta I inhibitor Go6976 induces dephosphorylation of constitutively hyperphosphorylated Rb and G1 arrest in
1University of Turku, Department of Ophthalmology, Turku, Finland.
Background:
Rb functions as a key controller of the G(1)-S transition of the cell cycle, and its inactivation leads to a defective G(1) checkpoint. Bladder cancer frequently displays alterations in Rb such as constitutive hyperphosphorylation which results in inactive Rb and progression of cells to the S-phase. Several protein kinase C (PKC) inhibitors are currently undergoing clinical trials as anticancer drugs.
Materials And Methods:
T24 urinary bladder carcinoma cells, known to express hyperphosphorylated Rb, were treated with PKCα/βI inhibitor Go6976. The treated cells were subjected to cell cycle analysis, cell growth assay and Western blots for Rb and cdc2 phosphorylation.
Results:
The treatment resulted in Rb dephosphorylation at Ser 795 and Ser 807/811, and cdc2 dephosphorylation at Tyr15. Subsequent G(0/1) arrest and reduced proliferation rates were observed.
Conclusion:
The results show that Go6976 can be used to restore constantly hyperphosphorylated and therefore constantly inactive Rb function in cancer cells.
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