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The natural compound atraric acid suppresses androgen-regulated neo-angiogenesis of castration-resistant prostate cancer through angiopoeitin2

ABSTRACT: Castration-resistant prostate cancer (CRPC) is an incurable form of prostate cancer (PC) and a major therapeutic challenge. Here, we show that the natural compound, atraric acid (AA), inhibits besides the androgen receptor (AR) those AR-mutants that confer therapy resistance to AR-antagonists indicating a different mode of AR-antagonism. AA induces cellular senescence and inhibits intratumoral angiogenesis and CRPC tumour growth in treated xenograft mice. RNA-seq reveals an upregulated angiogenic transcriptional pathway by androgen. In line with this, conditioned medium from CRPC cells induces angiogenesis in two in vitro models using primary human endothelial cells. By employing immune arrays and mass-spec analyses, we found that androgens induced secretion of pro-angiogenic factors pinpointing to angiopoeitin2 (ANGPT2). The senescence-associated secretory phenotype revealed reduced ANGPT2 secretion by AA. Accordingly, immune-depletion of ANGPT2 or blocking ANGPT2-receptors inhibits angiogenesis. Our data propose AA as potential anti-PCa compound and ANGPT2 pathway as novel therapeutic target for CRPC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE151492 | GEO | 2021/08/31

REPOSITORIES: GEO

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Project description:Continued androgen receptor (AR) signaling is an established mechanism underlying castration-resistant prostate cancer (CRPC), and suppression of AR signaling remains a therapeutic goal of CRPC therapy. Constitutively active androgen receptor splicing variants (AR-Vs) lack the AR ligand-binding domain (AR-LBD), the intended target of androgen deprivation therapies (ADT) including new CRPC therapies such as abiraterone and MDV3100. While the canonical full-length AR (AR-FL) and AR-Vs are both increased in CRPC, their expression regulation, associated transcriptional programs, functional relationships, and respective roles in mediating responses to endocrine therapies have not been dissected. In this study, we show that suppression of canonical AR-FL signaling by targeting AR-LBD leads to increased AR-V expression in two cell line models of CRPC. Importantly, treatment-induced AR-Vs activate a distinct expression signature enriched for cell cycle genes without requiring the presence of AR-FL. Conversely, activation of AR-FL signaling suppresses the AR-V signature but activates expression programs mainly associated with macromolecular synthesis, metabolism, and differentiation. In prostate cancer cells and CRPC xenografts treated with MDV3100 and abiraterone, increased expression of two constitutively active AR-Vs, AR-V7 and ARV567ES, but not AR-FL, parallels increased expression of the AR-driven cell cycle gene UBE2C. In addition, protein expression of AR-V7, but not AR-FL, is positively correlated with UBE2C in clinical CRPC specimens. The cumulative in vitro and in vivo evidence support an adaptive shift toward AR-V-mediated signaling in at least a subset of CRPC tumors as the AR-LBD is rendered inactive, suggesting an important mechanism contributing to drug resistance to CRPC therapies. LNCaP cells lacking AR-V were transfected with AR-V7 with or without androgen stimulation of AR-FL (4 conditions); LNCaP95 cells expressing AR-Vs were treated with control siRNA or siRNA trageting AR-LBD or AR-DBD, with or without androgen stimulation of AR-FL (6 conditions); VCaP cells expressing AR-Vs in the presence of androgen were treated with control siRNA, siRNA trageting AR-LBD, DMSO or MDV3100 to inhibit AR-FL (4 conditions). Total 14 arrays with no replicates.

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The natural compound atraric acid suppresses androgen-regulated neo-angiogenesis of castration-resistant prostate cancer through angiopoeitin2

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