BACKGROUND: In order for tumors to grow and proliferate, they must avoid recognition by immune cells and subsequent death by apoptosis. Granzyme B (GrB), a protease located in natural killer cells, initiates apoptosis in target cells. Inhibition of GrB by PI-9, its natural inhibitor, can prevent apoptosis. Here we investigate whether PI-9 protects prostate cancer cells from apoptosis. METHODS: The expression of PI-9 was quantified by qPCR in several prostate cancer cell lines, and GrB activity was tested in each cell line. PI-9 was overexpressed in LNCaP cells, which lack endogenous PI-9. Apoptosis was induced by natural killer cells in LNCaP cells that either contained or lacked PI-9, and the percent cell death was quantified. Lastly, PI-9 levels were examined by qPCR and immunohistochemistry in prostate tumor tissue. RESULTS: Prostate cancer cell lines that expressed PI-9 could inhibit GrB. Overexpression of PI-9 protected LNCaP cells from natural killer cell-mediated apoptosis. Examination of the levels of PI-9 in tissue from prostate tumors showed that PI-9 could be upregulated in low grade tumors and stochastically dysregulated in high grade tumors. Additionally, PI-9 was found consistently in high grade prostatic intraepithelial neoplasia and atrophic lesions. CONCLUSIONS: These results indicate that overexpression of PI-9 can protect prostate cancer cells from apoptosis, and this effect may occur in human prostate tumors. These findings imply that early prostatic inflammation may trigger this increase in PI-9. This suggests that PI-9 upregulation is needed early in tumor progression, before additional protective mechanisms are in place.
BACKGROUND: In order for tumors to grow and proliferate, they must avoid recognition by immune cells and subsequent death by apoptosis. Granzyme B (GrB), a protease located in natural killer cells, initiates apoptosis in target cells. Inhibition of GrB by PI-9, its natural inhibitor, can prevent apoptosis. Here we investigate whether PI-9 protects prostate cancer cells from apoptosis. METHODS: The expression of PI-9 was quantified by qPCR in several prostate cancer cell lines, and GrB activity was tested in each cell line. PI-9 was overexpressed in LNCaP cells, which lack endogenous PI-9. Apoptosis was induced by natural killer cells in LNCaP cells that either contained or lacked PI-9, and the percent cell death was quantified. Lastly, PI-9 levels were examined by qPCR and immunohistochemistry in prostate tumor tissue. RESULTS:Prostate cancer cell lines that expressed PI-9 could inhibit GrB. Overexpression of PI-9 protected LNCaP cells from natural killer cell-mediated apoptosis. Examination of the levels of PI-9 in tissue from prostate tumors showed that PI-9 could be upregulated in low grade tumors and stochastically dysregulated in high grade tumors. Additionally, PI-9 was found consistently in high grade prostatic intraepithelial neoplasia and atrophic lesions. CONCLUSIONS: These results indicate that overexpression of PI-9 can protect prostate cancer cells from apoptosis, and this effect may occur in humanprostate tumors. These findings imply that early prostatic inflammation may trigger this increase in PI-9. This suggests that PI-9 upregulation is needed early in tumor progression, before additional protective mechanisms are in place.
Authors: Christopher A Willoughby; Herbert G Bull; Margarita Garcia-Calvo; Joanne Jiang; Kevin T Chapman; Nancy A Thornberry Journal: Bioorg Med Chem Lett Date: 2002-08-19 Impact factor: 2.823
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Authors: B A Bladergroen; M C Strik; N Bovenschen; O van Berkum; G L Scheffer; C J Meijer; C E Hack; J A Kummer Journal: J Immunol Date: 2001-03-01 Impact factor: 5.422
Authors: Joost J Oudejans; Hari Harijadi; J Alain Kummer; I Bing Tan; Elizabeth Bloemena; Jaap M Middeldorp; Belinda Bladergroen; Danny F Dukers; Wim Vos; Chris J L M Meijer Journal: J Pathol Date: 2002-12 Impact factor: 7.996
Authors: J P Medema; J de Jong; L T Peltenburg; E M Verdegaal; A Gorter; S A Bres; K L Franken; M Hahne; J P Albar; C J Melief; R Offringa Journal: Proc Natl Acad Sci U S A Date: 2001-09-18 Impact factor: 11.205