Inhibiting geranylgeranyl diphosphate synthesis reduces nuclear androgen receptor signaling and neuroendocrine differentiation in prostate cancer cell models

Weissenrieder, Jillian; Reilly, Jacqueline E.; Neighbors, Jeffrey D.; Hohl, Raymond J.

doi:10.1002/pros.23707

Cited by 10 publications

(6 citation statements)

References 49 publications

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“…Western blot analysis was carried out as described previously using the ScanLater (Molecular Devices, San Jose, CA, USA) system 13 . Membranes were incubated with primary antibodies for D 2 R (1:1000 dilution, Millipore Sigma, Burlington, MA, USA), and vinculin (1:1000 dilution, Cell Signaling Technology) overnight at 4°C after blocking.…”

Section: Methodsmentioning

confidence: 99%

“…Western blot analysis was carried out as described previously using the ScanLater (Molecular Devices, San Jose, CA, USA) system. 13 Membranes were incubated with primary antibodies for D 2 R (1:1000 dilution, Millipore Sigma, Burlington, MA, USA), and vinculin (1:1000 dilution, Cell Signaling Technology) overnight at 4°C after blocking. Eu-conjugated secondary antibodies (Molecular Devices) were applied for one hour at room temperature before rinsing, drying, and reading membranes on a SpectraMax i3x (Molecular Devices).…”

Section: Immunoblottingmentioning

confidence: 99%

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Antipsychotic drugs elicit cytotoxicity in glioblastoma multiforme in a calcium‐dependent, non‐D₂ receptor‐dependent, manner

Weissenrieder

Reed

Moldovan

et al. 2021

Pharmacology Res & Perspec

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Dopamine D 2 -like receptor antagonists have been suggested as being potential anticancer therapeutics with specific utility for central nervous system cancers due to their ability to cross the blood-brain barrier. Despite a plethora of data reporting anticancer effects for D 2 R antagonists in cell or animal studies, the ligand concentrations or doses required to achieve such effects greatly exceed the levels known to cause high degrees of occupancy of the D 2 receptor. To resolve this conundrum, we interrogated a panel of glioblastoma multiforme (GBM) cell lines using D 2 antagonists of varying chemotype. We studied the cytotoxic effects of these compounds, and also ascertained the expression of D 2 receptors (D 2 R) on these cells. Although several chemotypes of D 2 R antagonists, including phenothiazines and phenylbutylpiperidines, were effective against GBM cell line cultures, the highly selective antagonist remoxipride had no anticancer activity at biologically relevant concentrations. Moreover the D 2 R antagonist-induced cytotoxicity in monolayer cultures was independent of whether the cells expressed D 2 R. Instead, cytotoxicity was associated with a rapid, high-magnitude calcium flux into the cytoplasm and mitochondria, which then induced depolarization and apoptosis. Blocking this flux protected the GBM cell lines U87MG, U251MG, and A172. Together, these data suggest that the cytotoxicity of these D 2 R antagonists involves calcium signaling mechanisms, not D 2 R antagonism. Repurposing of existing drugs should focus on the former, not latter, mechanism.

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Section: Methodsmentioning

confidence: 99%

Section: Immunoblottingmentioning

confidence: 99%

Antipsychotic drugs elicit cytotoxicity in glioblastoma multiforme in a calcium‐dependent, non‐D₂ receptor‐dependent, manner

Weissenrieder

Reed

Moldovan

et al. 2021

Pharmacology Res & Perspec

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“…The second generation of AR pathway inhibitors, such as enzalutamide and abiraterone, were commonly used for high-risk locally or systemically advanced CaP (Borgmann et al, 2018;Hussain et al, 2018;Alpajaro et al, 2019;Mateo et al, 2019). Thus, targeting AR with more specific and higher affinity compound to block AR-mediated downstream signaling becomes desirable for therapeutic improvement on prostate oncology (Dalal et al, 2018;Weissenrieder et al, 2019). Therefore, utilizing the characteristic of maspin-mediated AR repression appropriately could open a new avenue for AR-related CaP management.…”

Section: Discussionmentioning

confidence: 99%

Tumor Suppressive Maspin-Sensitized Prostate Cancer to Drug Treatment Through Negative Regulating Androgen Receptor Expression

Tang¹,

Lian²,

Jiang³

et al. 2020

Front. Cell Dev. Biol.

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Overactivation of androgen receptor (AR)-mediated signal has been extensively implicated in prostate cancer (CaP) development, progression, and recurrence, which makes it an attractive therapeutic target. Meanwhile, as an endogenous inhibitor of histone deacetylase 1 (HDAC 1), tumor-suppressive mammary serine protease inhibitor (maspin) was reported to sensitize drug-induced apoptosis with a better therapeutic outcome in CaP, but the relationship between AR and maspin remains unclear. In the current study, treatment of 5-Aza or MS-275/enzalutamide induced poly (ADP-ribose) polymerase (PARP) cleavage and p-H2A.X in CaP cells with an increase of maspin expression but a decrease of AR. Then, treatment with protease inhibitor MG132 did not rescue the above drug-induced loss of AR. In addition, modulation of maspin expression by gene recombinant or siRNA technology showed an inverse correlation between expression of maspin and AR, consequently affecting the AR-regulated downstream gene transcription (e.g., NKX3.1 and TMPRSS2). Bioinformatics analysis of the data extracted from the National Center for Biotechnology Information Gene Expression Omnibus (NCBI GEO) database also revealed an inverse correlation between low maspin expression and high AR level in advanced CaP. Furthermore, chromatin immunoprecipitation (ChIP) assay using anti-maspin antibody identified that a portion of AR promoter sequence was co-precipitated and presented in the immunoprecipitated complex. Finally, maspin-mediated repression of AR was induced by treatment of MS-275, which promoted enzalutamide treatment efficacy with decrease of prostate-specific antigen (PSA) expression in LNCaP and 22RV1 cells. Taken together, the data not only demonstrated maspin-mediated repression of AR to augment drug anti-tumor activity but also provided in-depth support for combination of HDAC inhibitors with AR antagonist in CaP therapy.

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“…Western blotting was carried out with the Molecular Devices ScanLater system (San Jose, CA), as described previously 40 . Briefly, cells were harvested in RIPA buffer with protease and phosphatase inhibitors and agitated for an hour at 4 °C before protein quantification with a Pierce BCA (bicinchoninic acid) assay.…”

Section: Methodsmentioning

confidence: 99%

RNAseq reveals extensive metabolic disruptions in the sensitive SF-295 cell line treated with schweinfurthins

Weissenrieder

Weissenkampen

Reed

et al. 2022

Sci Rep

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The schweinfurthin family of natural compounds exhibit a unique and potent differential cytotoxicity against a number of cancer cell lines and may reduce tumor growth in vivo. In some cell lines, such as SF-295 glioma cells, schweinfurthins elicit cytotoxicity at nanomolar concentrations. However, other cell lines, like A549 lung cancer cells, are resistant to schweinfurthin treatment up to micromolar concentrations. At this time, the precise mechanism of action and target for these compounds is unknown. Here, we employ RNA sequencing of cells treated with 50 nM schweinfurthin analog TTI-3066 for 6 and 24 h to elucidate potential mechanisms and pathways which may contribute to schweinfurthin sensitivity and resistance. The data was analyzed via an interaction model to observe differential behaviors between sensitive SF-295 and resistant A549 cell lines. We show that metabolic and stress-response pathways were differentially regulated in the sensitive SF-295 cell line as compared with the resistant A549 cell line. In contrast, A549 cell had significant alterations in response genes involved in translation and protein metabolism. Overall, there was a significant interaction effect for translational proteins, RNA metabolism, protein metabolism, and metabolic genes. Members of the Hedgehog pathway were differentially regulated in the resistant A549 cell line at both early and late time points, suggesting a potential mechanism of resistance. Indeed, when cotreated with the Smoothened inhibitor cyclopamine, A549 cells became more sensitive to schweinfurthin treatment. This study therefore identifies a key interplay with the Hedgehog pathway that modulates sensitivity to the schweinfurthin class of compounds.

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Inhibiting geranylgeranyl diphosphate synthesis reduces nuclear androgen receptor signaling and neuroendocrine differentiation in prostate cancer cell models

Abstract: 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.

Cited by 10 publications

References 49 publications

Antipsychotic drugs elicit cytotoxicity in glioblastoma multiforme in a calcium‐dependent, non‐D₂ receptor‐dependent, manner

Antipsychotic drugs elicit cytotoxicity in glioblastoma multiforme in a calcium‐dependent, non‐D₂ receptor‐dependent, manner

Tumor Suppressive Maspin-Sensitized Prostate Cancer to Drug Treatment Through Negative Regulating Androgen Receptor Expression

RNAseq reveals extensive metabolic disruptions in the sensitive SF-295 cell line treated with schweinfurthins

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Inhibiting geranylgeranyl diphosphate synthesis reduces nuclear androgen receptor signaling and neuroendocrine differentiation in prostate cancer cell models

Abstract: 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.

Cited by 10 publications

References 49 publications

Antipsychotic drugs elicit cytotoxicity in glioblastoma multiforme in a calcium‐dependent, non‐D2 receptor‐dependent, manner

Antipsychotic drugs elicit cytotoxicity in glioblastoma multiforme in a calcium‐dependent, non‐D2 receptor‐dependent, manner

Tumor Suppressive Maspin-Sensitized Prostate Cancer to Drug Treatment Through Negative Regulating Androgen Receptor Expression

RNAseq reveals extensive metabolic disruptions in the sensitive SF-295 cell line treated with schweinfurthins

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Antipsychotic drugs elicit cytotoxicity in glioblastoma multiforme in a calcium‐dependent, non‐D₂ receptor‐dependent, manner

Antipsychotic drugs elicit cytotoxicity in glioblastoma multiforme in a calcium‐dependent, non‐D₂ receptor‐dependent, manner