Lipogenic effects of androgen signaling in normal and malignant prostate

Prostate cancer is an androgen-dependent cancer with unique metabolic features compared to many other solid tumors, and typically does not exhibit the “Warburg effect”. During malignant transformation, an early metabolic switch diverts the dependence of normal prostate cells on aerobic glycolysis for the synthesis of and secretion of citrate towards a more energetically favorable metabolic phenotype, whereby citrate is actively oxidised for energy and biosynthetic processes (i.e. de novo lipogenesis). It is now clear that lipid metabolism is one of the key androgen-regulated processes in prostate cells and alterations in lipid metabolism are a hallmark of prostate cancer, whereby increased de novo lipogenesis accompanied by over expression of lipid metabolic genes are characteristic of primary and advanced disease. Despite recent advances in our understanding of altered lipid metabolism in prostate tumorigenesis and cancer progression, the intermediary metabolism of the normal prostate and its relationship to androgen signaling remains poorly understood. In this review, we discuss the fundamental metabolic relationships that are distinctive in normal versus malignant prostate tissues, and the role of androgens in the regulation of lipid metabolism at different stages of prostate tumorigenesis.Chui YanMah, Zeyad D.Nassar, Johannes V.Swinnen, Lisa M.Butle

Разработка станций и проведение на них исследований по облучению микросхем и радиобиологии пучками ионов низких и высоких энергий ускорительного комплекса NICA

The aim of this study was to evaluate the impact of androgen ablation therapy in different prostate cancer (PCa) cell lines-reflecting different stages of the disease-on (18)F-fluorodeoxyglucose (FDG), (11)C-choline and (11)C-acetate uptake. Uptake experiments were performed in androgen-sensitive (LNCaP, PC346C) and independent cell lines (22Rv1, PC346DCC, PC-3) as well as in a benign prostatic hyperplasia (BPH-1) cell line. Tracer uptake was assessed under androgen ablation. Results of the cancer cell lines were normalized to those of BPH-1. To evaluate the effect of androgen on the uptake of (18)F-FDG, (11)C-choline and (11)C-acetate in PCa cell lines, 10(-8)M R1881, 10(-10)M R1881, the combination of 10(-10)M R1881 plus 10(-6)M Casodex or 10(-6)M Casodex alone were added in parallel cell cultures 1 day before uptake experiments. Uptake in androgen-supplemented cell cultures was compared to the uptake under androgen deprivation. Uptake was corrected for cell number using protein content. Compared to BPH-1, a higher (18)F-FDG uptake was observed only in PC346C cells, whereas a higher (11)C-choline and markedly increased (11)C-acetate uptake was seen in all cancer cell lines. Androgens significantly modulated the uptake of (18)F-FDG in LNCaP, PC346C and 22Rv1 cells, and of (11)C-choline in the PC346C and 22Rv1 cell line. No androgenic effect on (11)C-choline and (18)F-FDG uptake was observed in PC-3 and PC346DCC cells. (11)C-Acetate uptake was independent of androgen status in all PCa cell lines studied. (18)F-FDG uptake in PCa cell lines showed the highest variability and strongest androgen effect, suggesting its poor potential for metabolic imaging of advanced PCa. In contrast to (18)F-FDG and (11)C-choline, (11)C-acetate uptake was unaffected by androgens and thus (11)C-acetate seems best for monitoring PCa progression

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

Fatty acid β-oxidation (FAO) is the main bioenergetic pathway in human prostate cancer (PCa) and a promising novel therapeutic vulnerability. Here we demonstrate therapeutic efficacy of targeting FAO in clinical prostate tumors cultured ex vivo, and identify DECR1, encoding the rate-limiting enzyme for oxidation of polyunsaturated fatty acids (PUFAs), as robustly overexpressed in PCa tissues and associated with shorter relapse-free survival. DECR1 is a negatively-regulated androgen receptor (AR) target gene and, therefore, may promote PCa cell survival and resistance to AR targeting therapeutics. DECR1 knockdown selectively inhibited β-oxidation of PUFAs, inhibited proliferation and migration of PCa cells, including treatment resistant lines, and suppressed tumor cell proliferation and metastasis in mouse xenograft models. Mechanistically, targeting of DECR1 caused cellular accumulation of PUFAs, enhanced mitochondrial oxidative stress and lipid peroxidation, and induced ferroptosis. These findings implicate PUFA oxidation via DECR1 as an unexplored facet of FAO that promotes survival of PCa cells.Zeyad D Nassar, Chui Yan Mah, Jonas Dehairs, Ingrid JG Burvenich ... Lisa M Butler ... Luke Selth ... et al

Stearoyl-CoA desaturase-1 impairs the reparative properties of macrophages and microglia in the brain

Failure of remyelination underlies the progressive nature of demyelinating diseases such as multiple sclerosis. Macrophages and microglia are crucially involved in the formation and repair of demyelinated lesions. Here we show that myelin uptake temporarily skewed these phagocytes toward a disease-resolving phenotype, while sustained intracellular accumulation of myelin induced a lesion-promoting phenotype. This phenotypic shift was controlled by stearoyl-CoA desaturase-1 (SCD1), an enzyme responsible for the desaturation of saturated fatty acids. Monounsaturated fatty acids generated by SCD1 reduced the surface abundance of the cholesterol efflux transporter ABCA1, which in turn promoted lipid accumulation and induced an inflammatory phagocyte phenotype. Pharmacological inhibition or phagocyte-specific deficiency of Scd1 accelerated remyelination ex vivo and in vivo. These findings identify SCD1 as a novel therapeutic target to promote remyelination

Monounsaturated fatty acids: key regulators of cell viability and intracellular signalling in cancer.

Cancer cells feature increased macromolecular biosynthesis to support the formation of new organelles and membranes for cell division. In particular, lipids are key macromolecules that comprise cellular membrane components, substrates for energy generation and mediators of inter- and intracellular signaling. The emergence of more sensitive and accurate technology for profiling the “lipidome” of cancer cells has led to unprecedented leaps in understanding the complexity of cancer metabolism, but also highlighted promising therapeutic vulnerabilities. Notably, fatty acids, as lipid building blocks, are critical players in all stages of cancer development and progression and the importance of fatty acid desaturation and its impact on cancer cell biology has been well established. Recent years have seen the reports of new mechanistic insights into the role of monounsaturated fatty acids (MUFA) in cancer, as regulators of cell death and lipid-related cellular signaling. This commentary aims to highlight these diverse roles of MUFAs in cancer cells which may yield new directions for therapeutic interventions involving these important fatty acids.Julia S. Scott, Zeyad D. Nassar, Johannes V. Swinnen, and Lisa M. Butle

Unravelling Prostate Cancer Heterogeneity Using Spatial Approaches to Lipidomics and Transcriptomics

Published: 27 March 2022Due to advances in the detection and management of prostate cancer over the past 20 years, most cases of localised disease are now potentially curable by surgery or radiotherapy, or amenable to active surveillance without treatment. However, this has given rise to a new dilemma for disease management; the inability to distinguish indolent from lethal, aggressive forms of prostate cancer, leading to substantial overtreatment of some patients and delayed intervention for others. Driving this uncertainty is the critical deficit of novel targets for systemic therapy and of validated biomarkers that can inform treatment decision-making and to select and monitor therapy. In part, this lack of progress reflects the inherent challenge of undertaking target and biomarker discovery in clinical prostate tumours, which are cellularly heterogeneous and multifocal, necessitating the use of spatial analytical approaches. In this review, the principles of mass spectrometry-based lipid imaging and complementary gene-based spatial omics technologies, their application to prostate cancer and recent advancements in these technologies are considered. We put in perspective studies that describe spatially-resolved lipid maps and metabolic genes that are associated with prostate tumours compared to benign tissue and increased risk of disease progression, with the aim of evaluating the future implementation of spatial lipidomics and complementary transcriptomics for prognostication, target identification and treatment decision-making for prostate cancer.Shadrack M. Mutuku, Xander Spotbeen, Paul J. Trim, Marten F. Snel, Lisa M. Butler and Johannes V. Swinne

Androgenic regulation of lipid elongation in prostate cancer

AbstractZeyad D Nassar, Margaret M Centenera, Jelle Machiels, Samuel J Polacek, Katarzyna Bloch, Wayne D Tilley, Luke A Selth, Lisa M Butler, and Johannes V Swinne