Glucocorticoid receptor activity contributes to resistance to androgen-targeted therapy in prostate cancer.
Glucocorticoid receptor activity contributes to resistance to androgen-targeted therapy in prostate cancer.
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DOI：
10.1007/s12672-014-0173-2
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发表时间：
2014-04
影响因子：
3
通讯作者：
Szmulewitz RZ
中科院分区：
文献类型：
--
作者：
Isikbay M;Otto K;Kregel S;Kach J;Cai Y;Vander Griend DJ;Conzen SD;Szmulewitz RZ
尽管去势抵抗性前列腺癌（CRPC）有新的治疗方法，但由于对雄激素受体（AR）导向治疗的获得性耐药性，CRPC患者的预后仍然很差。糖皮质激素受体（GR）和AR共享几个转录靶点，包括抗凋亡基因血清和糖皮质激素调节激酶1（SGK 1）和Map激酶磷酸酶1（MKP 1）/双特异性磷酸酶1（DUSP 1）。由于GR表达增加的一个子集的原发性前列腺癌（PC）雄激素剥夺治疗后，我们试图确定是否GR激活可以有助于抵抗AR导向治疗。我们研究了CWR-22 Rv 1和LAPC 4 AR/GR表达PC细胞系与雄激素R1881，AR拮抗剂MDV 3100，GR激动剂地塞米松，GR拮抗剂米非司酮和CORT 122928，或SGK 1抑制剂GSK 650394的组合治疗后。还在体内研究了稳定表达GR（NR 3C 1）靶向shRNA或异位SGK 1-Flag的细胞系。GR激活减弱了AR拮抗剂MDV 3100对肿瘤细胞活力的影响。此外，GR激活增加前列腺特异性抗原（PSA）分泌并诱导SGKI和MKP 1/DUSP基因表达。糖皮质激素介导的细胞活力减少GR拮抗剂或与SGK 1抑制剂GSK 650394的共同治疗。在体内，GR耗竭延迟去势抵抗性肿瘤形成，而SGK 1-Flag过表达PC异种移植物显示加速去势抵抗性肿瘤启动，支持SGK 1在GR介导的CRPC进展中的作用。我们研究了雄激素阻断治疗前后的几种PC模型，发现GR表达和活性的增加有助于促进肿瘤的PC细胞活力。GR调节的SGK 1表达增加似乎至少部分介导PC细胞存活增强。因此，GR和/或SGK 1抑制可能是AR阻断治疗CRPC的有用替代物。
Despite new treatments for castrate-resistant prostate cancer (CRPC), the prognosis of patients with CRPC remains bleak due to acquired resistance to androgen receptor (AR)-directed therapy. The glucocorticoid receptor (GR) and AR share several transcriptional targets, including the anti-apoptotic genes serum and glucocorticoid-regulated kinase 1 (SGK1) and Map kinase phosphatase 1 (MKP1)/dual specificity phosphatase 1 (DUSP1). Because GR expression increases in a subset of primary prostate cancer (PC) following androgen deprivation therapy, we sought to determine whether GR activation can contribute to resistance to AR-directed therapy. We studied CWR-22Rv1 and LAPC4 AR/GR-expressing PC cell lines following treatment with combinations of the androgen R1881, AR antagonist MDV3100, GR agonist dexamethasone, GR antagonists mifepristone and CORT 122928, or the SGK1 inhibitor GSK650394. Cell lines stably expressing GR (NR3C1)-targeted shRNA or ectopic SGK1-Flag were also studied in vivo. GR activation diminished the effects of the AR antagonist MDV3100 on tumor cell viability. In addition, GR activation increased prostate-specific antigen (PSA) secretion and induced SGKI and MKP1/DUSP gene expression. Glucocorticoid-mediated cell viability was diminished by a GR antagonist or by co-treatment with the SGK1 inhibitor GSK650394. In vivo, GR depletion delayed castrate-resistant tumor formation, while SGK1-Flag-overexpressing PC xenografts displayed accelerated castrate-resistant tumor initiation, supporting a role for SGK1 in GR-mediated CRPC progression. We studied several PC models before and following treatment with androgen blockade and found that increased GR expression and activity contributed to tumor-promoting PC cell viability. Increased GR-regulated SGK1 expression appears, at least in part, to mediate enhanced PC cell survival. Therefore, GR and/or SGK1 inhibition may be useful adjuncts to AR blockade for treating CRPC.
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DOI：
10.1073/pnas.0709102105
发表时间：
2008-03-25
影响因子：
11.1
作者：
Jeanneteau, Freddy;Garabedian, Michael J.;Chao, Moses V.
通讯作者：
Chao, Moses V.
影响因子：
7.7
作者：
Balbas MD;Evans MJ;Hosfield DJ;Wongvipat J;Arora VK;Watson PA;Chen Y;Greene GL;Shen Y;Sawyers CL
通讯作者：
Sawyers CL
影响因子：
5.3
作者：
Andreu-Vieyra, Claudia;Lai, John;Coetzee, Gerhard A.
通讯作者：
Coetzee, Gerhard A.
影响因子：
64.5
作者：
Arora VK;Schenkein E;Murali R;Subudhi SK;Wongvipat J;Balbas MD;Shah N;Cai L;Efstathiou E;Logothetis C;Zheng D;Sawyers CL
通讯作者：
Sawyers CL
影响因子：
50.3
作者：
Carver BS;Chapinski C;Wongvipat J;Hieronymus H;Chen Y;Chandarlapaty S;Arora VK;Le C;Koutcher J;Scher H;Scardino PT;Rosen N;Sawyers CL
通讯作者：
Sawyers CL