Abstract
An increasing number of castration-resistant prostate cancer (CRPC) tumors exhibit neuroendocrine (NE) features. NE prostate cancer (NEPC) has poor prognosis, and its development is poorly understood.Experimental Design: We applied mass spectrometry-based proteomics to a unique set of 17 prostate cancer patient-derived xenografts (PDX) to characterize the effects of castration in vivo, and the proteome differences between NEPC and prostate adenocarcinomas. Genome-wide profiling of REST-occupied regions in prostate cancer cells was correlated to the expression changes in vivo to investigate the role of the transcriptional repressor REST in castration-induced NEPC differentiation. An average of 4,881 proteins were identified and quantified from each PDX. Proteins related to neurogenesis, cell-cycle regulation, and DNA repair were found upregulated and elevated in NEPC, while the reduced levels of proteins involved in mitochondrial functions suggested a prevalent glycolytic metabolism of NEPC tumors. Integration of the REST chromatin bound regions with expression changes indicated a direct role of REST in regulating neuronal gene expression in prostate cancer cells. Mechanistically, depletion of REST led to cell-cycle arrest in G1, which could be rescued by p53 knockdown. Finally, the expression of the REST-regulated gene secretagogin (SCGN) correlated with an increased risk of suffering disease relapse after radical prostatectomy. This study presents the first deep characterization of the proteome of NEPC and suggests that concomitant inhibition of REST and the p53 pathway would promote NEPC. We also identify SCGN as a novel prognostic marker in prostate cancer.
Highlights
Death in prostate cancer patients mostly occurs after the development of castration-resistant metastatic disease (CRPC)
Quantitative proteomic data can cluster patient–derived xenografts (PDX) by origin and hormone status We analyzed the proteome of 17 prostate cancer PDX tumors, of which 4 tumors were obtained 3 weeks after castration of the host and in 2 cases tumors relapsed after castration and were collected
The proteome of PDX LTL-331 after 3 weeks of castration (LTL-331-X) shows higher similarity to tumors with NE prostate cancer (NEPC) PDXs (LTL-370 and LTL-352), than to the parental untreated PDX (LTL-331), suggesting that a castration-induced transdifferentiation process occurred in this case (Fig. 1C)
Summary
Death in prostate cancer patients mostly occurs after the development of castration-resistant metastatic disease (CRPC). Castration-resistant tumors develop after androgen ablation therapy or. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Extensive studies have been carried out to identify tumor driving genetic alterations in CRPC, but a unified genetic model of disease progression is yet to emerge. Amplification of the AR gene locus or point mutations in the AR gene occurs in 60% of tumors that have been subjected to androgen ablation therapy [3]. Other common genetic alterations in AR-expressing CRPC include heterozygous deletions of PTEN and, to a lesser extent, p53 inactivation or loss of Rb1 expression [5,6,7,8]
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