The fat side of prostate cancer

Abstract

Prostate cancer (PCa) metabolism appears to be unique in comparison with other type of solid cancers. Normal prostate cells mainly rely on glucose oxidation to provide precursors for the synthesis and secretion of citrate, resulting in an incomplete Krebs cycle and minimal oxidative phosphorylation for energy production. In contrast, during transformation, PCa cells no longer secrete citrate and they reactivate the Krebs cycle as energy source. Moreover, primary PCas do not show increased aerobic glycolysis and therefore they are not efficiently detectable with 18F-FDG-PET. However, increased de novo lipid synthesis, strictly intertwined with deregulation in classical oncogenes and oncosuppressors, is an early event of the disease. Up-regulation and increased activity of lipogenic enzymes (including fatty acid synthase and choline kinase) occurs throughout PCa carcinogenesis and correlates with worse prognosis and poor survival. Thus, lipid precursors such as acetate and choline have been successfully used as alternative tracers for PET imaging. Lipid synthesis intermediates and FA catabolism also emerged as important players in PCa maintenance. Finally, epidemiologic studies suggested that systemic metabolic disorders including obesity, metabolic syndrome, and diabetes as well as hypercaloric and fat-rich diets might increase the risk of PCa. However, how metabolic disorders contribute to PCa development and whether dietary lipids and de novo lipids synthesized intra-tumor are differentially metabolized still remains unclear. In this review, we examine the switch in lipid metabolism supporting the development and progression of PCa and we discuss how we can exploit its lipogenic nature for therapeutic and diagnostic purposes.

Organ-Specific Cancer Metabolism and Its Potential for Therapy

“…Advanced, relapsing and castration-insensitive prostate cancers are largely treated with therapies that target the androgen signaling pathway and immune therapy (reviewed in [115,116]). In addition, more attempts to develop drugs that act on other prostate cancer targets, such as ETS-fusions, or the PI3K signaling pathway, or fatty acid metabolism, are reported [117,118]. Prostate cancer originates in the peripheral zone of the prostate where about 70% of the cancer emerges in a multifocal manner [119].…”

“…Further dedifferentiation of the tumor is connected with a more pronounced expression of monocarboxylase transporter 1, lactate dehydrogenase A, altered cholesterol metabolism [147], as well as with a boost in fatty acid biosynthesis and associated enzymes (reviewed in [118]). Moreover, inhibition of fatty acid biosynthesis and oxidation was reported to inhibit tumor growth [143,148,149].…”

Androgen control of lipid metabolism in prostate cancer: novel insights and future applications

“…One of the cellular processes most strikingly affected by androgens is lipid metabolism , Zadra et al 2013. For many years, it has been noted by nuclear magnetic resonance spectroscopy that clinical prostate tumors, particularly more advanced and aggressive cases, often exhibit intense lipid signals, denoted as 'mobile lipids'.…”

“…FASN in particular has received considerable attention as a potential therapeutic target (Mullen & Yet 2015) and small molecule inhibitors of FASN, including the antiobesity agent orlistat, have demonstrated promising preclinical efficacy in prostate tumor models (reviewed in Menendez & Lupu (2007), Zadra et al (2013), Wu et al (2014)). Unfortunately, despite active drug discovery efforts, the clinical translation of these agents to date has been limited by unacceptable toxicity profiles (Mullen & Yet 2015).…”

Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL)-Troglitazone-induced Apoptosis in Prostate Cancer Cells Involve AMP-activated Protein Kinase

“…Androgen deprivation therapy is the currently used therapeutic option for treating advanced PCa. Although the tumors initially respond to this therapeutic regimen, they eventually become androgen-independent and thus castration-resistant (2). The median survival rate of men with metastatic castration-resistant PCa (CRPC) is less than 2 years (3) with no effective drugs currently available to treat these resistant forms.…”