Inhibition of Granzyme B by PI-9 protects prostate cancer cells from apoptosis.
Inhibition of Granzyme B by PI-9 protects prostate cancer cells from apoptosis.
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DOI：
10.1002/pros.21486
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发表时间：
2012-06-01
期刊：
影响因子：
2.8
通讯作者：
Craik, Charles S.
中科院分区：
文献类型：
--
作者：
Ray, Manisha;Hostetter, Daniel R.;Loeb, Carly R. K.;Simko, Jeffry;Craik, Charles S.
为了使肿瘤生长和增殖，它们必须避免被免疫细胞识别并随后通过细胞凋亡而死亡。颗粒酶 B 是一种位于自然杀伤细胞中的蛋白酶，可启动靶细胞的凋亡。颗粒酶 B 的天然抑制剂 PI-9 对其的抑制可以防止细胞凋亡。在这里，我们研究 PI-9 是否可以保护前列腺癌细胞免于凋亡。通过 qPCR 对几种前列腺癌细胞系中 PI-9 的表达进行定量，并测试每个细胞系中的粒酶 B 活性。 PI-9 在缺乏内源 PI-9 的 LNCaP 细胞中过度表达。含有或缺乏 PI-9 的 LNCaP 细胞中的自然杀伤细胞诱导细胞凋亡，并对细胞死亡百分比进行量化。最后，通过 qPCR 和免疫组织化学检测前列腺肿瘤组织中的 PI-9 水平。表达 PI-9 的前列腺癌细胞系可以抑制颗粒酶 B。PI-9 的过度表达可保护 LNCaP 细胞免受自然杀伤细胞介导的细胞凋亡。对前列腺肿瘤组织中 PI-9 水平的检查表明，PI-9 在低级别肿瘤中可能上调，而在高级别肿瘤中随机失调。此外，PI-9 始终存在于高级前列腺上皮内瘤变和萎缩性病变中。这些结果表明PI-9的过度表达可以保护前列腺癌细胞免于凋亡，并且这种作用可能发生在人类前列腺肿瘤中。这些发现意味着早期前列腺炎症可能会引发 PI-9 的增加。这表明在肿瘤进展早期，在额外的保护机制到位之前，需要上调 PI-9。
In order for tumors to grow and proliferate, they must avoid recognition by immune cells and subsequent death by apoptosis. Granzyme B, a protease located in natural killer cells, initiates apoptosis in target cells. Inhibition of Granzyme B 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 Granzyme B 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 in 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 Granzyme B. 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 is 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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影响因子：
4.8
作者：
Kannan-Thulasiraman, P;Shapiro, DJ
通讯作者：
Shapiro, DJ
影响因子：
4.8
作者：
Harris, JL;Peterson, EP;Craik, CS
通讯作者：
Craik, CS
DOI：
10.1073/pnas.201398198
发表时间：
2001-09-25
影响因子：
11.1
作者：
Medema, JP;de Jong, J;Offringa, R
通讯作者：
Offringa, R
影响因子：
4.3
作者：
Cunningham, Thomas D.;Jiang, Xinguo;Shapiro, David J.
通讯作者：
Shapiro, David J.
DOI：
10.4049/jimmunol.0903789
发表时间：
2010-04-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Liu G;Atteridge CL;Wang X;Lundgren AD;Wu JD
通讯作者：
Wu JD