Inhibition of Granzyme B by PI-9 protects prostate cancer cells from apoptosis

Graduate Group in Biochemistry and Molecular Biology, University of California, San Francisco, California 94158-2517, USA.
The Prostate (Impact Factor: 3.57). 06/2012; 72(8):846-55. DOI: 10.1002/pros.21486
Source: PubMed


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.
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.
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.
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.

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Available from: Charles S Craik, Mar 29, 2015
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