Pim-1: A Molecular Target to Modulate Cellular Resistance to Therapy in Prostate Cancer
Abstract
The contract supports studies to define the role of the Pim-1 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 JAK1/2 activation, STAT3 phosphorylation, expression of Pim-1, and activation of NFkB signaling. Blockade of this pathway by expression of dominant negative Pim-1 proteins blocks drug-induced upregulation of NFkB activity, and sensitizes cells to docetaxel. Other studies (specific aim #2) focus on identifying a mechanism through which Pim-1 activates NFkB. We have unambiguously identified S937 as the major Pim-1 phosphorylation site on the NFKB1/p105 precursor protein, through use of LCM/MS/MS analysis. Other kinases that can phosphorylate this site include AKT and PKA. Additional data (specific aim #3) have been published to describe a small molecule inhibitor of Pim-1. This molecule can sensitize prostate cancer cells to the cytotoxic effects of docetaxel in an additive or synergistic manner.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2006
- Accession Number
- ADA465489
Entities
People
- Michael B. Lilly
Organizations
- Loma Linda University