Androgen-regulated expression of arginase 1, arginase 2 and interleukin-8 in human prostate cancer.
Androgen-regulated expression of arginase 1, arginase 2 and interleukin-8 in human prostate cancer.
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DOI：
10.1371/journal.pone.0012107
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发表时间：
2010-08-11
期刊：
影响因子：
3.7
通讯作者：
Mes-Masson AM
中科院分区：
文献类型：
--
作者：
Gannon PO;Godin-Ethier J;Hassler M;Delvoye N;Aversa M;Poisson AO;Péant B;Alam Fahmy M;Saad F;Lapointe R;Mes-Masson AM
前列腺癌（PCa）是北美男性中最常见的癌症。雄激素剥夺疗法（ADT）加重了前列腺内免疫细胞的浸润。然而，雄激素在前列腺癌中调节的免疫抑制途径还没有得到很好的表征。PCa细胞的精氨酸酶2（ARG 2）表达导致肿瘤特异性T细胞的活化减少。我们的假设是雄激素可以调节前列腺癌细胞ARG 2的表达。在这份报告中，我们证明了ARG 1和ARG 2都表达的肿瘤敏感性（HS）和肿瘤难治性（HR）PCa细胞系，与LNCaP细胞具有最高的β-淀粉酶活性。在前列腺组织样本中，与肿瘤组织相比，ARG 2在正常和非恶性前列腺组织中表达更多。用10 nM R1881对LNCaP细胞进行雄激素刺激后，ARG 1和ARG 2均过表达。雄激素刺激后对ARG酶表达的调节依赖于雄激素受体（AR），因为靶向AR的siRNA治疗可抑制ARG 1和ARG 2的过表达。通过免疫组织化学在患者体内观察到了相关性。术前接受ADT治疗的患者在非恶性和恶性组织中的ARG 2表达均较低。此外，ARG 1和ARG 2具有酶活性，siRNA降低了它们的表达，导致总体精氨酸酶活性和L-精氨酸代谢降低。ARG 1和ARG 2表达的降低也伴随着LNCaP细胞生长的减少和暴露于LNCaP细胞条件培养基后PBMC活化的增加。最后，我们发现白细胞介素-8（IL-8）在雄激素刺激后也上调，并且在雄激素缺乏的情况下直接增加ARG 1和ARG 2的表达。我们的数据提供了第一个详细的体外和体内帐户的雄激素调节免疫抑制途径在人类前列腺癌通过表达ARG 1，ARG 2和IL-8。
Prostate cancer (PCa) is the most frequently diagnosed cancer in North American men. Androgen-deprivation therapy (ADT) accentuates the infiltration of immune cells within the prostate. However, the immunosuppressive pathways regulated by androgens in PCa are not well characterized. Arginase 2 (ARG2) expression by PCa cells leads to a reduced activation of tumor-specific T cells. Our hypothesis was that androgens could regulate the expression of ARG2 by PCa cells. In this report, we demonstrate that both ARG1 and ARG2 are expressed by hormone-sensitive (HS) and hormone-refractory (HR) PCa cell lines, with the LNCaP cells having the highest arginase activity. In prostate tissue samples, ARG2 was more expressed in normal and non-malignant prostatic tissues compared to tumor tissues. Following androgen stimulation of LNCaP cells with 10 nM R1881, both ARG1 and ARG2 were overexpressed. The regulation of arginase expression following androgen stimulation was dependent on the androgen receptor (AR), as a siRNA treatment targeting the AR inhibited both ARG1 and ARG2 overexpression. This observation was correlated in vivo in patients by immunohistochemistry. Patients treated by ADT prior to surgery had lower ARG2 expression in both non-malignant and malignant tissues. Furthermore, ARG1 and ARG2 were enzymatically active and their decreased expression by siRNA resulted in reduced overall arginase activity and l-arginine metabolism. The decreased ARG1 and ARG2 expression also translated with diminished LNCaP cells cell growth and increased PBMC activation following exposure to LNCaP cells conditioned media. Finally, we found that interleukin-8 (IL-8) was also upregulated following androgen stimulation and that it directly increased the expression of ARG1 and ARG2 in the absence of androgens. Our data provides the first detailed in vitro and in vivo account of an androgen-regulated immunosuppressive pathway in human PCa through the expression of ARG1, ARG2 and IL-8.
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影响因子：
3.9
作者：
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