Weissenrieder Jillian S, Reilly Jacqueline E, Neighbors Jeffrey D, Hohl Raymond J
Departments of Medicine and Pharmacology, Penn State College of Medicine, Hershey, Pennsylvania.
Department of Pharmacology, University of Iowa, Iowa City, Iowa.
Prostate. 2019 Jan;79(1):21-30. doi: 10.1002/pros.23707. Epub 2018 Aug 14.
Following androgen deprivation for the treatment of advanced adenocarcinoma of the prostate, tumors can progress to neuroendocrine prostate cancer (NEPC). This transdifferentiation process is poorly understood, but trafficking of transcriptional factors and/or cytoskeletal rearrangements may be involved. We observed the role of geranylgeranylation in this process by treatment with digeranyl bisphosphonate (DGBP), a selective inhibitor of geranylgeranyl pyrophosphate synthase which blocks the prenylation of small GTPases such as Rho and Rab family proteins, including Cdc42 and Rac1.
We examined the therapeutic potential of DGBP in LNCaP, C4-2B4, and 22Rv1 cell culture models. Cell morphology and protein expression were quantified to observe the development of the neuroendocrine phenotype in androgen-deprivation and abiraterone-treated LNCaP models of NEPC development. Luciferase reporter assays were utilized to examine AR activity, and immunofluorescence visualized the localization of AR within the cell.
Essential genes in the isoprenoid pathway, such as HMGCR, MVK, GGPS1, and GGT1, were highly expressed in a subset of castration resistant prostate cancers reported by Beltran et al. Under treatment with DGBP, nuclear localization of AR decreased in LNCaP, 22Rv1, and C4-2B4 cell lines, luciferase reporter activity was reduced in LNCaP and 22Rv1, and AR target gene transcription also decreased in LNCaP. Conversely, nuclear localization of AR was enhanced by the addition of GGOH. Finally, induction of the NEPC structural and molecular phenotype via androgen deprivation in LNCaP cells was inhibited by DGBP in a GGOH-dependent manner.
DGBP is a novel compound with the potential to reduce AR transcriptional activity and inhibit PCa progression to NEPC phenotype. These results suggest that DGBP may be used to block cell growth and metastasis in both hormone therapy sensitive and resistant paradigms.
在采用雄激素剥夺疗法治疗晚期前列腺腺癌后，肿瘤可能进展为神经内分泌前列腺癌（NEPC）。这种转分化过程目前了解甚少，但可能涉及转录因子的转运和/或细胞骨架重排。我们通过用香叶基香叶基双膦酸盐（DGBP）处理来观察香叶基香叶基化在此过程中的作用，DGBP是香叶基香叶基焦磷酸合酶的选择性抑制剂，可阻断小GTP酶（如Rho和Rab家族蛋白，包括Cdc42和Rac1）的异戊二烯化。
我们在LNCaP、C4 - 2B4和22Rv1细胞培养模型中研究了DGBP的治疗潜力。对细胞形态和蛋白表达进行定量，以观察在雄激素剥夺和阿比特龙治疗的LNCaP NEPC发展模型中神经内分泌表型的发展情况。利用荧光素酶报告基因检测来检测AR活性，免疫荧光观察AR在细胞内的定位。
类异戊二烯途径中的关键基因，如HMGCR、MVK、GGPS1和GGT1，在Beltran等人报道的一部分去势抵抗性前列腺癌中高表达。在用DGBP处理后，LNCaP、22Rv1和C4 - 2B4细胞系中AR的核定位减少，LNCaP和22Rv1中的荧光素酶报告基因活性降低，LNCaP中AR靶基因转录也减少。相反，添加GGOH可增强AR的核定位。最后，DGBP以GGOH依赖的方式抑制了LNCaP细胞中通过雄激素剥夺诱导的NEPC结构和分子表型。
DGBP是一种新型化合物，具有降低AR转录活性和抑制前列腺癌进展为NEPC表型的潜力。这些结果表明，DGBP可用于在激素治疗敏感和耐药模式下阻断细胞生长和转移。
