Abstract #3474: Modulation of senescence of prostate tumor cells by the PIM1 protein kinase. Free

PIM1 is a serine/threonineprotein kinase that mediates survival and proliferation signals in response to growth factors and to cellular stresses. Elevated PIM1 expression has been implicated in tumor development of human cancers, including prostate cancer, lymphoma, leukemia, multiple myeloma, pancreatic cancer and colon cancer. The recent studies have shown that PIM1 can behave as a dominant oncogene that is capable of activating of the p53 pathway, leading to oncogene-induced senescence in mouse embryonic fibroblasts. To identify the molecular events associated with constitutive expression of PIM1 in prostate epithelium, we have generated stable pools of human prostate cell lines transduced with retroviruses carrying human PIM1 or empty vector. After 10 weeks of incubation 22RV1/PIM1 prostate cells expressing wild type p53 underwent complete growth arrest, while other cell lines which have mutant or lower levels of p53 protein showed only a slight delay (DU145, RWPE-1) or no difference (RWPE-2) in growth ratio compared with the vector transfected cells. We investigated the levels of proteins associated with senescence in these cells p21^CIP1, p16^INK4A and p27^KIP1 in PIM1 expressing cells. In 22Rv1/PIM1 cells we find an increased level of p21^CIP1 protein and 5-fold increase of p21^CIP1 mRNA but no major change in p16^INK4A or p27^KIP1 . DU145/PIM1 and RWPE-1/PIM1 cell lines contained the same the levels of p21 and p16^INK4A as control cell lines. In contrast the amount of p21^CIP1 was significantly reduced in RWPE-2 cells co-expressing both the K-RAS and PIM1 oncogenes. We suggest that PIM1 kinase may modulate growth of prostate cancer cells through a p53-dependent p21^CIP1 pathway, and PIM1 may work synergistically with other oncogenes in the prostate cancer cell growth. To identify cooperating pathways in Pim mediated prostate cancer growth and possibly transformation, we have generated lentiviruses and retroviruses carrying inducible PIM1, AKT and RAS genes. These experiments will clarify the extent to which enforced expression of PIM1 requires AKT and RAS oncogenes to modulate cell growth in p53 wild type and null cells.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3474.