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The natural compound atraric acid suppresses androgen-regulated neo-angiogenesis of castration‑resistant prostate cancer through angiopoietin 2

ABSTRACT: Castration‑resistant prostate cancer (CRPC) is an aggressive lethal form of prostate cancer (PCa), which presents a major therapeutic challenge. Here, we show that the natural compound, atraric acid (AA), inhibits not only the androgen receptor (AR) but also targets those AR-mutants that confer therapy resistance to other clinically used AR-antagonists indicating a different mode of AR-antagonism. AA induces cellular senescence in CRPC and inhibits CRPC tumour growth in vivo xenograft model. The secretome of CRPC cells induces androgen-dependent angiogenesis, which is counteracted by AA regulated senescence-associated secretory phenotype (SASP) in two in vitro models using primary human endothelial cells. In line with this, in tumours, vessel number is decreased in the mouse group treated with AA suggesting the repression of intratumoural neo-angiogenesis by AA. Transcriptome sequencing and mass spec analysis of the secretome revealed upregulated angiogenic pathways by androgen, however, being VEGF-independent and pointing to the secretion of the pro-angiogenic factor angiopoietin 2 (ANGPT2) induced by androgens and repressed by AA as a key driver of neo-angiogenesis. In agreement with this, AA treatment of native patient-derived PCa tumour samples ex vivo inhibits ANGPT2 expression. Mechanistically, besides AA, immune-depletion of ANGPT2 or blocking ANGPT2-receptors inhibits androgen-induced angiogenesis. Taken together, we reveal a VEGF-independent ANGPT2 pathway targeted by AA to inhibit androgen-regulated neo-angiogenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE172205 | GEO | 2022/06/23

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 angiopoietin 2

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