Pim-1: A Molecular Target to Modulate Cellular Resistance to Therapy in Prostate Cancer
Annual rept. 1 Oct 2004-30 Sep 2005
LOMA LINDA UNIV CA
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The contract supports studies to define the role of the PIM1 kinase in acquired resistance to chemotherapy by prostate cancer cells. Data to date for specific aim 1 define a signaling pathway induced by docetaxel, involving sequential steps of STAT3 activation, expression of PIM1, and activation of NFkB signaling. Blockade of this pathway by expression of dominant negative PIM1proteins blocks drug-induced upregulation of NFkB activity, and sensitizes cells to docetaxel. Other studies specific aim 2 focus on identifying a mechanism through which PIM1 activates NFkB. We have unambiguously identified S937 as the major PIM1 phosphorylation site on the NFKB1p105 precursor protein, through use of LCMMSMS analysis. Interestingly PIM2 is only a weak kinase for this site. Additional data specific aim 3 have been generated to characterize a small molecule inhibitor of PIM1.
- Medicine and Medical Research