p53-dependent induction of prostate cancer cell senescence by the PIM1 protein kinase

Marina Zemskova, Michael B. Lilly, Ying Wei Lin, Jin H. Song, Andrew Kraft

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

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 β-galactosidase (SA-β-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 γH2AX 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-β-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.

Original languageEnglish (US)
Pages (from-to)1126-1141
Number of pages16
JournalMolecular Cancer Research
Volume8
Issue number8
DOIs
StatePublished - Aug 2010
Externally publishedYes

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Cell Aging
Protein Kinases
Prostatic Neoplasms
DNA Damage
Galactosidases
Proteins
Polyploidy
Protein-Serine-Threonine Kinases
p53 Genes
Growth
Interleukin-8
Genetic Markers
Small Interfering RNA
Prostate
Interleukin-6
Neoplasms
Carcinogenesis
Phosphorylation
Apoptosis
Cell Line

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Oncology

Cite this

p53-dependent induction of prostate cancer cell senescence by the PIM1 protein kinase. / Zemskova, Marina; Lilly, Michael B.; Lin, Ying Wei; Song, Jin H.; Kraft, Andrew.

In: Molecular Cancer Research, Vol. 8, No. 8, 08.2010, p. 1126-1141.

Research output: Contribution to journalArticle

Zemskova, Marina ; Lilly, Michael B. ; Lin, Ying Wei ; Song, Jin H. ; Kraft, Andrew. / p53-dependent induction of prostate cancer cell senescence by the PIM1 protein kinase. In: Molecular Cancer Research. 2010 ; Vol. 8, No. 8. pp. 1126-1141.
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