PKCalpha/beta I inhibitor Go6976 induces dephosphorylation of constitutively hyperphosphorylated Rb and G1 arrest in T24 cells.

Abstract

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.

• Authors: V Aaltonen, J Peltonen
• Journal: Anticancer research (Anticancer Res) Vol. 30 Issue 10 Pg. 3995-9 (Oct 2010) ISSN: 1791-7530 [Electronic] Greece
• PMID: 21036713 (Publication Type: Journal Article)

Chemical References

• Carbazoles
• Protein Kinase Inhibitors
• Retinoblastoma Protein
• Go 6976
• Protein Kinase C
• Protein Kinase C beta
• Protein Kinase C-alpha
• Maturation-Promoting Factor

Topics

• Carbazoles (pharmacology)
• Carcinoma, Transitional Cell (drug therapy, enzymology, metabolism, pathology)
• Cell Line, Tumor
• Flow Cytometry
• G1 Phase (drug effects)
• Genes, p53
• Humans
• Maturation-Promoting Factor (metabolism)
• Mutation
• Phosphorylation (drug effects)
• Protein Kinase C (antagonists & inhibitors, metabolism)
• Protein Kinase C beta
• Protein Kinase C-alpha (antagonists & inhibitors, metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Retinoblastoma Protein (metabolism)
• Urinary Bladder Neoplasms (drug therapy, enzymology, metabolism, pathology)