Prostate cancer castrate resistant progression usage of non-canonical androgen receptor signaling and ketone body fuel

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.

Integrative Molecular Analyses of the MD Anderson Prostate Cancer Patient-derived Xenograft (MDA PCa PDX) Series

“…IGV sashimi plots were used to identify putative ARv7 variants (≥5 reads). We confirmed the presence of ARv7 by IHC, using standard techniques ( 11 ) and anti-ARv7 antibody, clone RM7 (RevMab Biosciences, RRID:AB_2716436). Staining was evaluated by semiquantitative analysis of pattern, percentage of cells, and intensity on a scale of 1 to 3.…”

“…S6A). Accordingly, we previously reported that a metabolic shift occurs in an Ad PDX during CRPC relapse ( 11 ).…”

“…For histology, organoids were fixed with 10% formalin ON, transferred to 70% ethanol, and paraffin embedded. Hematoxylin and eosin and IHC using anti-AR antibody (Agilent, M3562, RRID:AB_2060174) were performed using standard techniques ( 11 ).…”

Integrative Metabolomic Analysis of Serum and Selected Serum Exosomal microRNA in Metastatic Castration-Resistant Prostate Cancer

“…Interestingly, Saraon et al (2013) identified the ketogenic pathway as a novel bioenergetic pathway potentially involved in the progression of PC from a low-grade to a high-grade disease, followed by androgen independence [ 58 ]. Moreover, increased expression of both ketogenic and ketolytic enzymes (acetyl-CoA acetyltransferase 1, ACAT1; 3-hydroxybutyrate dehydrogenase 1, BDH1; 3-hydroxymethyl-3-methylglutaryl-CoA lyase, HMGCL; and 3-oxoacid CoA-transferase 1, OXCT1) was reported with PC progression, gradually increasing with the tumor grade [ 58 , 59 ]. Huang et al (2017) showed that serum 3-hydroxybutyrate was associated with an increased risk of fatal PC in men diagnosed with metastatic disease [ 38 ].…”

Construction of a prognostic signature for serous ovarian cancer based on lactate metabolism-related genes

“…BDH1(3-Hydroxybutyrate Dehydrogenase 1) is a key enzyme that regulates the metabolism and synthesis of ketone bodies. Studies found that expression of BDH1 was also associated with decreased time to biochemical relapse and decreased progression-free survival ( 33 ). PPARGC1A (PPARG Coactivator 1 Alpha), also known as PGC-1α, is highly expressed in ovarian cancer cells, some researchers showed its high expression in cisplatin-resistant cells ( 34 ), while some others revealed its overexpression could induce cell apoptosis ( 35 ).…”