2,4-dienoyl-CoA reductase regulates lipid homeostasis in treatment-resistant prostate cancer

Abstract

Despite the clinical success of Androgen Receptor (AR)-targeted therapies, reactivation of AR signalling remains the main driver of castration-resistant prostate cancer (CRPC) progression. In this study, we perform a comprehensive unbiased characterisation of LNCaP cells chronically exposed to multiple AR inhibitors (ARI). Combined proteomics and metabolomics analyses implicate an acquired metabolic phenotype common in ARI-resistant cells and associated with perturbed glucose and lipid metabolism. To exploit this phenotype, we delineate a subset of proteins consistently associated with ARI resistance and highlight mitochondrial 2,4-dienoyl-CoA reductase (DECR1), an auxiliary enzyme of beta-oxidation, as a clinically relevant biomarker for CRPC. Mechanistically, DECR1 participates in redox homeostasis by controlling the balance between saturated and unsaturated phospholipids. DECR1 knockout induces ER stress and sensitises CRPC cells to ferroptosis. In vivo, DECR1 deletion impairs lipid metabolism and reduces CRPC tumour growth, emphasizing the importance of DECR1 in the development of treatment resistance.

Human DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis

“…Here, we show that the ferroptosis inhibitors ferrostatin and deferoxamine or the ferroptosis inducers erastin, FIN56 and ML210 abolished and augmented the effect of DECR1 on PCa cell death, respectively. These findings are consistent with a mechanism by which DECR1 knockdown-induced cell death is a ferroptosis-mediated process caused by PUFA accumulation, a conclusion that was independently validated in human prostate cancer during revision of this article ( Blomme et al, 2020 ). It is therefore possible that PCa cells commonly select for DECR1 overexpression, not only to enhance ATP production to fulfil energy requirements, but also to protect cells from the tumoricidal effects of excess PUFAs.…”

Schlafen family member 5 (SLFN5) regulates LAT1-mediated mTOR activation in castration-resistant prostate cancer

“…BCAA catabolism serves to replenish the tricarboxylic acid cycle and is dysregulated in PCa 32 , while targeting FA metabolism has been proposed as a therapeutic option in the context of CRPC and enzalutamide resistance 33, 34 . Ferroptosis, another lipid-related process that has recently been suggested as an important resistance mechanism against AR targeted therapies 6 , was also enriched in our CRPC models. Likewise, peroxisome proliferator-activated receptor (PPAR) signalling was commonly enriched in all three models of CRPC orthografts.…”

“…Increased SLFN5 expression was also observed in vitro following long-term androgen deprivation (Figure 2c). AR is the main driver of ADT resistance 6 and directly regulates the expression of multiple genes involved in a plethora of biological processes that, if aberrantly regulated, are known to cause cancer pathogenesis 21 . Therefore we tested the ability of AR to modulate SLFN5 expression in PCa cells.…”

Schlafen family member 5 (SLFN5) regulates LAT1-mediated mTOR activation in castration-resistant prostate cancer

“…BCAA catabolism serves to replenish the tricarboxylic acid cycle and is dysregulated in PCa 32 , while targeting FA metabolism has been proposed as a therapeutic option in the context of CRPC and enzalutamide resistance 33,34 . Ferroptosis, another lipid-related process that has recently been suggested as an important resistance mechanism against AR targeted therapies 6 , was also enriched in our CRPC models. Likewise, peroxisome proliferatoractivated receptor (PPAR) signalling was commonly enriched in all three models of CRPC orthografts.…”