Abstract
Prostate cancer (PCa) that progresses after androgen deprivation therapy (ADT) remains incurable. The underlying mechanisms that account for the ultimate emergence of resistance to ADT, progressing to castrate-resistant prostate cancer (CRPC), include those that reactivate androgen receptor (AR), or those that are entirely independent or cooperate with androgen signaling to underlie PCa progression. The intricacy of metabolic pathways associated with PCa progression spurred us to develop a metabolism-centric analysis to assess the metabolic shift occurring in PCa that progresses with low AR expression. We used PCa patient-derived xenografts (PDXs) to assess the metabolic changes after castration of tumor-bearing mice and subsequently confirmed main findings in human donor tumor that progressed after ADT. We found that relapsed tumors had a significant increase in fatty acids and ketone body (KB) content compared with baseline. We confirmed that critical ketolytic enzymes (ACAT1, OXCT1, BDH1) were dysregulated after castrate-resistant progression. Further, these enzymes are increased in the human donor tissue after progressing to ADT. In an in silico approach, increased ACAT1, OXCT1, BDH1 expression was also observed for a subset of PCa patients that relapsed with low AR and ERG (ETS-related gene) expression. Further, expression of these factors was also associated with decreased time to biochemical relapse and decreased progression-free survival. Our studies reveal the key metabolites fueling castration resistant progression in the context of a partial or complete loss of AR dependence.
Highlights
Androgen signaling inhibition remains the mainstay, and patients are treated despite the known heterogeneity of responsiveness
Most importantly, when we studied the expression of ACAT1, oxoacid CoA-transferase 1 (OXCT1), and BDH1 in the human donor tumor of MDA Prostate cancer (PCa) 183, we detected significant increased expression of these enzymes in PCa progressing to androgen deprivation therapy (ADT) as compared with the untreated tumor of the same patient (Fig. 5D, E, P < 0.0001, P < 0.0001, P = 0.0033, respectively)
We have discovered that these metabolic alterations occur in cells that do Oncogene not use the canonical androgen receptor (AR) signaling while progressing to ADT
Summary
Androgen signaling inhibition remains the mainstay, and patients are treated despite the known heterogeneity of responsiveness. Progress in comprehending Likewise, in relapsed tumors AR expression remained low changes in the metabolic program during PCa progression has compared with control (P < 0.0001), with cytoplasmic and nuclear been hampered by a lack of models, representative of the localization, and ERG staining remained negative (P < 0.0001) (Fig. clinical spectrum and biologic complexity of PCa. Patient-derived 2B, C). From high glycolytic activity to exacerbated KB metabolism, indicating that a subpopulation of CRPCs that progress with Metabolomic shifts in PCa response to castration partial or complete loss of AR dependence are fueled by KB. We With the goal of understanding the metabolomic changes confirmed that expression of critical ketolytic enzymes was significantly augmented after castration-resistant progression in associated with PCa progression under ADT and identify the putative metabolites fueling CRPC, we used metabolomics both the PDX tumor and its human donor tissue. The comparison among groups using Welch’s two-sample t-test identified the following changes: 84 metabolites exhibited
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