Molecular Cancer esearch Cycle , Cell Death , and Senescence-Dependent Induction of Prostate Cancer Cell R escence by the PIM 1 Protein Kinase

ownload PIM family of serine threonine protein kinases plays an important role in regulating both the growth and rmation of malignant cells. However, in a cell line–dependent manner, overexpression of PIM1 can t cell and tumor growth. In 22Rv1 human prostate cells, but not in Du145 or RWPE-2, PIM1 oversion was associated with marked increases in cellular senescence, as shown by changes in the levels of ctosidase (SA-β-Gal), p21, interleukin (IL)-6 and IL-8 mRNA and protein. During early cell passages, induced cellular polyploidy. As the passage number increased, markers of DNA damage, including the f γH2AX and CHK2 phosphorylation, were seen. Coincident with these DNA damage markers, the level protein and genes transcriptionally activated by p53, such as p21, TP53INP1, and DDIT4, increased. In 2Rv1 cells, the induction of p53 protein was associated not only with senescence but also with a signifevel of apoptosis. The importance of the p53 pathway to PIM1-driven cellular senescence was further by the observation that expression of dominant-negative p53 or shRNA targeting p21 blocked the PIM1d changes in the DNA damage response and increases in SA-β-Gal activity. Likewise, in a subcutaneous model, PIM1-induced senescence was rescued when the p53-p21 pathways are inactivated. Based on tumor these results, PIM1 will have its most profound effects on tumorigenesis in situations where the senescence response is inactivated. Mol Cancer Res; 8(8); 1126–41. ©2010 AACR.