The Mechanism of Action of Unique Small Molecules that Inhibit the Pim Protein Kinase Blocking Prostate Cancer Cell Growth
Annual rept. 1 May 2009-30 Apr 2010
MEDICAL UNIV OF SOUTH CAROLINA CHARLESTON
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The Pim protein kinase is over expressed in prostate cancers. To clarify the role of this protein in regulating prostate cancer growth we have investigated its mechanism of action. Additionally, we have studied the ability of small molecule inhibitors of Pim developed in our laboratory to block the growth stimulatory affects of this protein kinase. We find that Pim-1 is able to decrease the levels of the cell cycle inhibitory protein p27 by phosphorylating Skp-2, the protein that regulates the level of p27,. Phosphorylation of Skp-2 prolongs the half-life of Skp-2, increases its levels, and enhances its ability to degrade p27. Pim also functions to stimulate the phosphorylation of the Cdc27 protein also inhibiting its function. Since active Cdc27 is needed for the destruction of Skp-2, this also increases Skp-2 and decreases the levels of p27. Low levels of p27 allow prostate cancer cells to rapidly transit the cell cycle. We find that our chemical inhibitor of Pim, SMI-4a, is able to reverse the activity of Pim-1 and increase the levels of p27. This data suggests that inhibition of Pim-1 by these agents would function to block prostate cancer growth by inhibiting transit through the cell cycle. Thus, our agent has potential activity to treat this cancer.
- Genetic Engineering and Molecular Biology
- Anatomy and Physiology
- Medicine and Medical Research