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ATF3 is a converging node for AR signaling and fatty acid oxidation in castration-resistant prostate cancer

ABSTRACT: Prostate cancer (PCa) is the second most prevalent cancer and leading causes of death among men worldwide. Androgen deprivation is the first line of treatment for locally advanced and metastatic PCa. For men who develop metastatic castration-resistant PCa (mCRPC), survival is limited. Thus, there is a need to identify synergistic pathways to either prevent or re-sensitize the castration-resistant phenotype. PCa has a long natural history of development and there is a significant correlation between age, diet, metabolism and progress of PCa. We have previously reported that treating PCa cells with fatty acid oxidation inhibitors (FAOi) sensitizes them to androgen blockade. Here we set out to evaluate how the two disparate pathways: AR signaling and FAO, influence one another hoping to identify new therapeutic vulnerabilities. We used CRPC cell models (LNCaP-MDV-resistant, and LNCaP-C4-2), as well as the FAOi (etomoxir and ranolazine) and the antiandrogen enzalutamide (MDV3100). Cells were treated for 48 hours, followed by gene expression, androgen signaling and growth analysis. Both FAOi strongly suppressed the androgen response hallmark in MDV-res cells, and this was associated with a significant upregulation of the ATF3 gene. Interestingly, knockdown (KD) of ATF3 with shRNAs resulted in differential responses to FAOi in these genetically-related cells. In the MDV-resistant cells, ATF3 KD resulted in increased PSA expression with FAOi treatment. On the other hand, in the C4-2 cells, ATF3 KD resulted in decreased PSA expression with FAOi treatment. These results suggested that ATF3 is a convergent point for AR and FAO pathways and that is cell-context dependent, and its expression status could be exploited to sensitize PCa cells to MDV3100 and/or the FAOi. Cell growth and apoptosis assays confirmed that the LNCaP-derived ATF3 KD were more sensitive to MDV3100 and FAOi compared to control cells. Examination of patient databases revealed an inverse correlation between AR and ATF3, a low expression of ATF3 in advanced cancers and better disease-free survival in patients with high ATF3 expression. These data support the role for FAOi to re-sensitize CRPC to endocrine therapies. In conclusion, we have identified ATF3 as a modulator of FAO and AR signaling that has predictive value for clinical outcomes using FAOi in CRPC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE124971 | GEO | 2022/04/01

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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ATF3 is a converging node for AR signaling and fatty acid oxidation in castration-resistant prostate cancer

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