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.
Highlights
Prostate cancer (PCa) is the second leading cause of cancer death in men in the US and the fifth cause worldwide [1]
While the majority of reports describe AR-mediated regulation of de novo Fatty acid (FA) synthesis in PCa progression, evidence is accumulating that both FA synthesis and FA oxidation (FAO) are regulated by AR signaling and contribute to castration resistance (CR) in a fine-tuned manner
In 2003, Swinnen and coworkers demonstrated that FASN plays a major role in the synthesis of PLs partitioning into detergent-resistant membrane microdomains, the latter being involved in key cellular processes including signal transduction, intracellular trafficking, cell polarization, and cell migration [45]
Summary
Prostate cancer (PCa) is the second leading cause of cancer death in men in the US and the fifth cause worldwide [1]. Treatments with PARP inhibitors have been recently approved by the U.S Food and Drug Administration (FDA) for the treatment of mCRPC patients harboring tumors with defects in DNA damage response (DDR), especially in the gene BRAC2, opening a new area for precision oncology in advanced PCa [5]. New mechanisms of therapy resistance and disease progression associated with lipid metabolism rewiring have recently emerged This has been supported by the recent advances in analytical techniques including high-resolution mass spectrometry (MS)-based lipidomics and MS-based imaging (MSI) that allow to measure hundreds of lipid species at once, Including rare lipid species, and to provide spatial resolution. The more we understand about these aspects the better we can develop strategies to counteract their tumor supportive functions while enhancing their health-promoting roles
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