Prostate Cancer Progression: as a Matter of Fats

Abstract

Advanced prostate cancer (PCa) represents the fifth cause of cancer death worldwide. Although survival has improved with second-generation androgen signaling and Parp inhibitors, the benefits are not long-lasting, and new therapeutic approaches are sorely needed. Lipids and their metabolism have recently reached the spotlight with accumulating evidence for their role as promoters of PCa development, progression, and metastasis. As a result, interest in targeting enzymes/transporters involved in lipid metabolism is rapidly growing. Moreover, the use of lipogenic signatures to predict prognosis and resistance to therapy has been recently explored with promising results. Despite the well-known association between obesity with PCa lethality, the underlying mechanistic role of diet/obesity-derived metabolites has only lately been unveiled. Furthermore, the role of lipids as energy source, building blocks, and signaling molecules in cancer cells has now been revisited and expanded in the context of the tumor microenvironment (TME), which is heavily influenced by the external environment and nutrient availability. Here, we describe how lipids, their enzymes, transporters, and modulators can promote PCa development and progression, and we emphasize the role of lipids in shaping TME. In a therapeutic perspective, we describe the ongoing efforts in targeting lipogenic hubs. Finally, we highlight studies supporting dietary modulation in the adjuvant setting with the purpose of achieving greater efficacy of the standard of care and of synthetic lethality. PCa progression is “a matter of fats”, and the more we understand about the role of lipids as key players in this process, the better we can develop approaches to counteract their tumor promoter activity while preserving their beneficial properties.

Lipid Metabolism and Epigenetics Crosstalk in Prostate Cancer

“…PCa is characterized by an increased de novo FA synthesis that has been associated with energy storage, redox balance, increased requirement by cell membranes, and regulation of many key cellular processes that are involved in cell proliferation, apoptosis, differentiation, angiogenesis, inflammation, motility, epithelial-mesenchymal transition, and drug resistance [36,57]. FA synthesis occurs in the cytosol and the first reaction is the conversion of citrate, derived from the mitochondrial TCA cycle, to acetyl-CoA by ATP citrate lyase (ACLY) [57].…”

“…Not only uptake of lipids from the circulation, but also de novo lipid synthesis, partly stimulated by androgens, play important roles in PCa and are correlated with tumour progression and poor prognosis [35,36]. In fact, aberrant metabolism is a hallmark of cancer, as tumour cells need to rewire their metabolism to satisfy the energy requirements and biochemical needs stemming from their uncontrolled growth and other oncogenic capacities [37].…”

From Omics to Multi-Omics Approaches for In-Depth Analysis of the Molecular Mechanisms of Prostate Cancer

“…Elevated de-novo lipogenesis is a hallmark of prostate cancer [ 186 ] and different lipid forms are up-regulated in cell lines derived from prostate cancer metastases [ 228 ]. Androgens impact lipid metabolism at diverse tumor stages and there is a unique dependence of prostate cancer on fatty acids to drive progression [ 226 , 229 , 230 , 231 , 232 ]. Lipid profiles can now be mapped almost to single-cell level and several studies show that extensive and heterogenous rewiring takes place in prostate tumors [ 233 ].…”

Fatty Acid Metabolism Reprogramming in Advanced Prostate Cancer

“…The key enzyme, stearoyl CoA desaturase (SCD), facilitates proliferation of prostate cancer cells through an AR dependent pathway [125,126]. An SCD1 inhibitor (BZ36) has been proven to repress the proliferation of LNCaP and C4-2 cells in vitro and in vivo through the phosphatidylinositol 3-kinase and AKT-dependent pathway [127,128]. Researchers have also studied long-chain acyl CoA synthetase (ACSL) enzymes in terms of their role in providing fatty acyl-CoAs, which are downstream metabolites of FA.…”