p53-dependent induction of prostate cancer cell senescence by the PIM1 protein kinase.
The PIM family of serine threonine protein kinases plays an important role in regulating both the growth and transformation of malignant cells. However, in a cell line-dependent manner, overexpression of PIM1 can inhibit cell and tumor growth. In 22Rv1 human prostate cells, but not in Du145 or RWPE-2, PIM1 overexpression was associated with marked increases in cellular senescence, as shown by changes in the levels of beta-galactosidase (SA-beta-Gal), p21, interleukin (IL)-6 and IL-8 mRNA and protein. During early cell passages, PIM1 induced cellular polyploidy. As the passage number increased, markers of DNA damage, including the level of gammaH2AX and CHK2 phosphorylation, were seen. Coincident with these DNA damage markers, the level of p53 protein and genes transcriptionally activated by p53, such as p21, TP53INP1, and DDIT4, increased. In these 22Rv1 cells, the induction of p53 protein was associated not only with senescence but also with a significant level of apoptosis. The importance of the p53 pathway to PIM1-driven cellular senescence was further shown by the observation that expression of dominant-negative p53 or shRNA targeting p21 blocked the PIM1-induced changes in the DNA damage response and increases in SA-beta-Gal activity. Likewise, in a subcutaneous tumor model, PIM1-induced senescence was rescued when the p53-p21 pathways are inactivated. Based on these results, PIM1 will have its most profound effects on tumorigenesis in situations where the senescence response is inactivated.
Zemskova
Marina
M
Department of Cell and Molecular Pharmacology, Hollings Cancer Center, Charleston, SC 29425, USA.
Lilly
Michael B
MB
Lin
Ying-Wei
YW
Song
Jin H
JH
Kraft
Andrew S
AS
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D019556:COS Cells; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence; D064447:Checkpoint Kinase 2; D002522:Chlorocebus aethiops; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005799:Genes, Dominant; D042822:Genomic Instability; D006801:Humans; D007124:Immunoenzyme Techniques; D016209:Interleukin-8 / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D010641:Phenotype; D011123:Polyploidy; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051573:Proto-Oncogene Proteins c-pim-1 / Q000378:metabolism* / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019076:Transgenes / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D001616:beta-Galactosidase / Q000378:metabolism
D050759:Cyclin-Dependent Kinase Inhibitor p21; D016209:Interleukin-8; C094167:Pim2 protein, mouse; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; C578633:Chek2 protein, mouse; C496634:PIM1 protein, human; C496636:Pim1 protein, mouse; C488192:Pim3 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051573:Proto-Oncogene Proteins c-pim-1; D001616:beta-Galactosidase