Characterization of novel cell lines derived from a MYC‐driven murine model of lethal metastatic adenocarcinoma of the prostate

Markowski, Mark C.; Hubbard, Gretchen K.; Hicks, Jessica L.; Zheng, Qizhi; King, Alexia; Esopi, David; Rege, Apurv; Yegnasubramanian, Srinivasan; Bieberich, Charles J.; Marzo, Angelo M. De

doi:10.1002/pros.23657

Cited by 4 publications

(6 citation statements)

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“…The BMPC mice develop castration resistance and lose expression of AR around 20 weeks of age. As observed in Figure C, cells isolated from BMPC tumors had negligible AR expression. We then treated BMPC‐1 cells with BMH‐21 for 48 hours.…”

Section: Resultsmentioning

confidence: 53%

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Effective targeting of RNA polymerase I in treatment‐resistant prostate cancer

et al. 2019

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Background Advanced prostate cancers depend on protein synthesis for continued survival and accelerated rates of metabolism for growth. RNA polymerase I (Pol I) is the enzyme responsible for ribosomal RNA (rRNA) transcription and a rate‐limiting step for ribosome biogenesis. We have shown using a specific and sensitive RNA probe for the 45S rRNA precursor that rRNA synthesis is increased in prostate adenocarcinoma compared to nonmalignant epithelium. We have introduced a first‐in‐class Pol I inhibitor, BMH‐21, that targets cancer cells of multiple origins, and holds potential for clinical translation. Methods The effect of BMH‐21 was tested in prostate cancer cell lines and in prostate cancer xenograft and mouse genetic models. Results We show that BMH‐21 inhibits Pol I transcription in metastatic, castration‐resistant, and enzalutamide treatment‐resistant prostate cancer cell lines. The genetic abrogation of Pol I effectively blocks the growth of prostate cancer cells. Silencing of p53, a pathway activated downstream of Pol I, does not diminish this effect. We find that BMH‐21 significantly inhibited tumor growth and reduced the Ki67 proliferation index in an enzalutamide‐resistant xenograft tumor model. A decrease in 45S rRNA synthesis demonstrated on‐target activity. Furthermore, the Pol I inhibitor significantly inhibited tumor growth and pathology in an aggressive genetically modified Hoxb13‐MYC|Hoxb13‐Cre|Ptenfl/fl (BMPC) mouse prostate cancer model. Conclusion Taken together, BMH‐21 is a novel promising molecule for the treatment of castration‐resistant prostate cancer.

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Section: Resultsmentioning

confidence: 53%

“…All cell lines used were authenticated by short tandem repeat analyses at the Johns Hopkins Genetic Resources Core Facility. BMPC‐1 cells were as in Markowski et al and were cultured in DMEM supplemented with 10% FBS.…”

Section: Methodsmentioning

confidence: 99%

Effective targeting of RNA polymerase I in treatment‐resistant prostate cancer

et al. 2019

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“…By unlocking the cell‐specific and context‐specific effects of androgen on MYC expression, this conceptual advancement provides rationales to the elusive AR transformation from cell differentiator to a proliferator. Physiologically, the upregulation of both AR and MYC has been linked to PCa oncogenic progression and androgen insensitivity 25–29 . Upon castration, the reversal of androgen repression of AR and MYC loci would result in their overexpression, seeding chromatin co‐occupancy in CRPC 30 .…”

Section: Discussionmentioning

confidence: 99%

Androgen receptor and MYC transcriptomes are equilibrated in multilayer regulatory circuitries in prostate cancer

Fu,

Wang,

Jia

et al. 2023

The Prostate

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BackgroundThe discovery of androgen receptor (AR) having transrepression effects completes the circle of its functionalities as a typical transcription factor, which intrinsically bears dual functions of activation and repression linked to co‐factor competition and redistribution. Indeed, AR dual functions are exemplified by locus‐wide regulation of the oncogenic 8q24‐MYC region.MethodsRT‐qPCR assay and public RNA‐profiling datasets were used to assess MYC transcription in androgen‐sensitive cell lines. Public ChIP‐seq and RNA‐Seq datasets were computed to evaluate AR‐MYC direct and indirect signatures. Gene sets in typical MYC and AR pathways were monitored to validate their cross‐talks. Bio‐informatics and chromosome conformation capture (3C) assay were performed in the AR gene locus to examine androgen‐elicited distal regulation. Finally, co‐factor re‐distribution were globally tracked between AR and MYC binding sites.ResultsIn this report, we found MYC responded negatively to androgen with hypersensitivity, rivaling AR natural functions as an innate androgen effector. Furthermore, both direct and indirect AR and MYC transcriptional programs were actively in equilibration. With established androgen‐mediated versus MYC‐mediated gene subsets, we validated AR and MYC pathways were both bidirectional and extensively entangled. In addition, we determined that the AR gene locus resembled the MYC gene region and both loci were androgen‐repressed via epigenetics and chromatin architectural alterations. Significantly, transcriptional factor profiling along the prostate cancer (PCa) genome exposed that PCa transcriptomes were dynamically equilibrated between AR‐binding site and MYC‐binding site.ConclusionTogether, our findings stratified AR‐MYC interactions that are extensively wired and intricately organized to compensate for essential PCa transcriptional programs and neutralize excessive signaling.

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“…Isaacs (Johns Hopkins University). BMPC1, BMPC2, cells were obtained from Angelo De Marzo (Johns Hopkins University) (32). All human cell lines used were authenticated at the Johns Hopkins Genetic Resources Core Facility via short tandem repeat profiling of 9 genomic loci with the GenePrint 10 System (Promega, Madison, WI) before use.…”

Section: Methodsmentioning

confidence: 99%

P2X4 Purinergic Receptors as a Therapeutic Target in Aggressive Prostate Cancer

Vidal

et al. 2021

Preprint

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Prostate cancer (PCa) remains a leading cause of cancer-related deaths in American men and treatment options for metastatic PCa are limited. There is a critical need to identify new mechanisms that contribute to PCa progression, that distinguish benign from lethal disease, and that have potential for therapeutic targeting. P2X4 belongs to the P2 purinergic receptor family that is commonly upregulated in cancer and is associated with poorer outcomes. Herein, we report that the P2X4 purinergic receptor is overexpressed in PCa, associated with PCa metastasis, and a driver of tumor development in vivo. We observed P2X4 protein expression primarily in epithelial cells of the prostate, a subset of CD66+ neutrophils, and most CD68+ macrophages. Our analysis of tissue microarrays representing 491 PCa cases demonstrated significantly elevated P2X4 expression in cancer compared to benign tissue spots, in prostatic intraepithelial neoplasia, in cancer from White compared to Black men, and in PCa with ERG positivity or with PTEN loss. High P2X4 expression in benign tissues was likewise associated with the development of metastasis after radical prostatectomy. Treatment with P2X4-specific agonist CTP increased transwell migration and invasion of PC3, DU145, and CWR22Rv1 PCa cells. P2X4 antagonist 5-BDBD treatment resulted in a dose-dependent decrease in viability of PC3, DU145, LNCaP, CWR22Rv1, TRAMP-C2, Myc-CaP, BMPC1, and BMPC2 cells and decreased DU145 cell migration and invasion. Knockdown of P2X4 attenuated growth, migration, and invasion of PCa cells. Finally, knockdown of P2X4 in Myc-CaP cells resulted in significantly attenuated subcutaneous allograft growth in FVB/NJ mice. Collectively, these data strongly support a role for the P2X4 purinergic receptor in PCa aggressiveness and identifies P2X4 as a candidate for therapeutic targeting.

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Characterization of novel cell lines derived from a MYC‐driven murine model of lethal metastatic adenocarcinoma of the prostate

Abstract: These cell lines are a novel model of androgen-insensitive prostatic adenocarcinoma driven by MYC over-expression and Pten loss.

Cited by 4 publications

References 36 publications

Effective targeting of RNA polymerase I in treatment‐resistant prostate cancer

Effective targeting of RNA polymerase I in treatment‐resistant prostate cancer

Androgen receptor and MYC transcriptomes are equilibrated in multilayer regulatory circuitries in prostate cancer

P2X4 Purinergic Receptors as a Therapeutic Target in Aggressive Prostate Cancer

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