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GRK2 enforces androgen receptor dependence in the prostate and prostate tumors.
Oncogene ( IF 6.9 ) Pub Date : 2020-01-20 , DOI: 10.1038/s41388-020-1159-x Adam J Adler 1 , Payal Mittal 1, 2 , Adam T Hagymasi 1, 3 , Antoine Menoret 1 , Chen Shen 1 , Federica Agliano 1 , Kyle T Wright 1 , James J Grady 4 , Chia-Ling Kuo 4 , Enrique Ballesteros 5 , Kevin P Claffey 6 , Anthony T Vella 1
Oncogene ( IF 6.9 ) Pub Date : 2020-01-20 , DOI: 10.1038/s41388-020-1159-x Adam J Adler 1 , Payal Mittal 1, 2 , Adam T Hagymasi 1, 3 , Antoine Menoret 1 , Chen Shen 1 , Federica Agliano 1 , Kyle T Wright 1 , James J Grady 4 , Chia-Ling Kuo 4 , Enrique Ballesteros 5 , Kevin P Claffey 6 , Anthony T Vella 1
Affiliation
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Metastatic tumors that have become resistant to androgen deprivation therapy represent the major challenge in treating prostate cancer. Although these recurrent tumors typically remain dependent on the androgen receptor (AR), non-AR-driven tumors that also emerge are particularly deadly and becoming more prevalent. Here, we present a new genetically engineered mouse model for non-AR-driven prostate cancer that centers on a negative regulator of G protein-coupled receptors that is downregulated in aggressive human prostate tumors. Thus, prostate-specific expression of a dominant-negative G protein-coupled receptor kinase 2 (GRK2-DN) transgene diminishes AR and AR target gene expression in the prostate, and confers resistance to castration-induced involution. Further, the GRK2-DN transgene dramatically accelerates oncogene-initiated prostate tumorigenesis by increasing primary tumor size, potentiating visceral organ metastasis, suppressing AR, and inducing neuroendocrine marker mRNAs. In summary, GRK2 enforces AR-dependence in the prostate, and the loss of GRK2 function in prostate tumors accelerates disease progression toward the deadliest stage.
中文翻译：
GRK2在前列腺和前列腺肿瘤中增强雄激素受体依赖性。
已经对雄激素剥夺疗法产生抗性的转移性肿瘤代表了治疗前列腺癌的主要挑战。尽管这些复发性肿瘤通常仍然依赖于雄激素受体（AR），但也出现的非AR驱动的肿瘤特别致命，并且变得更加普遍。在这里，我们提出了一种新的基因工程小鼠模型，用于非AR驱动的前列腺癌，该模型以侵略性人前列腺肿瘤中下调的G蛋白偶联受体的负调节剂为中心。因此，显性阴性G蛋白偶联受体激酶2（GRK2-DN）转基因的前列腺特异性表达减少了AR中的AR和AR靶基因表达，并赋予了对去势诱导的对合的抗性。进一步，GRK2-DN转基因通过增加原发肿瘤大小，增强内脏器官转移，抑制AR并诱导神经内分泌标记物mRNA来显着加速癌基因引发的前列腺癌的发生。总而言之，GRK2在前列腺中增强了AR依赖性，并且前列腺肿瘤中GRK2功能的丧失加速了疾病发展到最致命的阶段。
更新日期：2020-01-21
中文翻译：
GRK2在前列腺和前列腺肿瘤中增强雄激素受体依赖性。
已经对雄激素剥夺疗法产生抗性的转移性肿瘤代表了治疗前列腺癌的主要挑战。尽管这些复发性肿瘤通常仍然依赖于雄激素受体（AR），但也出现的非AR驱动的肿瘤特别致命，并且变得更加普遍。在这里，我们提出了一种新的基因工程小鼠模型，用于非AR驱动的前列腺癌，该模型以侵略性人前列腺肿瘤中下调的G蛋白偶联受体的负调节剂为中心。因此，显性阴性G蛋白偶联受体激酶2（GRK2-DN）转基因的前列腺特异性表达减少了AR中的AR和AR靶基因表达，并赋予了对去势诱导的对合的抗性。进一步，GRK2-DN转基因通过增加原发肿瘤大小，增强内脏器官转移，抑制AR并诱导神经内分泌标记物mRNA来显着加速癌基因引发的前列腺癌的发生。总而言之，GRK2在前列腺中增强了AR依赖性，并且前列腺肿瘤中GRK2功能的丧失加速了疾病发展到最致命的阶段。
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