Abstract | BACKGROUND: METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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Authors | Jillian S Weissenrieder, Jacqueline E Reilly, Jeffrey D Neighbors, Raymond J Hohl |
Journal | The Prostate
(Prostate)
Vol. 79
Issue 1
Pg. 21-30
(01 2019)
ISSN: 1097-0045 [Electronic] United States |
PMID | 30106164
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | © 2018 Wiley Periodicals, Inc. |
Chemical References |
- Diphosphonates
- Polyisoprenyl Phosphates
- Receptors, Androgen
- Terpenes
- digeranyl bisphosphonate
- geranylgeranyl pyrophosphate
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Topics |
- Cell Differentiation
(drug effects, physiology)
- Cell Line, Tumor
- Cell Nucleus
(drug effects, metabolism)
- Diphosphonates
(pharmacology, therapeutic use)
- Dose-Response Relationship, Drug
- Humans
- Male
- Neuroendocrine Cells
(drug effects, metabolism)
- Polyisoprenyl Phosphates
(antagonists & inhibitors, biosynthesis)
- Prostatic Neoplasms
(drug therapy, metabolism)
- Receptors, Androgen
(metabolism)
- Signal Transduction
(drug effects, physiology)
- Terpenes
(pharmacology, therapeutic use)
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