Fatty acids role in cancer: Stearoyl-CoA desaturase 5 and its product oleic acid reduce melanoma dissemination by impairing tumor microenvironment

ABSTRACT Breakthroughs in the understanding of the basic biology of melanoma have yielded continue progresses on a variety of fronts. In the past decade, several specific inhibitors have been utilized against melanoma. However, after a short period of remission, their clinical use inevitably evidenced drug resistance and disease exacerbation. Finding new arms against the advanced phase of melanoma is one of the major challenges in the struggle against this cancer. New insight highlighted the rewiring of cellular signaling and the reprogramming of metabolic pathways in cancer. In normal cells a precise balance between saturated and unsaturated Fatty Acid (FA) synthesis is required for maintaining cell homeostasis. Conversely the anabolic pathways responsible for constructing these molecules appear altered during tumorigenesis. It is now appreciated the importance of fatty acid regulation in malignant disease and the opportunities to target these pathways, required not only for cell growth and division, but also for tumor dissemination. The role of the stearoyl-CoA desaturase 5 (SCD5) was investigated in melanoma, being its pathophysiological function virtually unknown. This enzyme, converting saturated into monounsaturated FAs, is downregulated during progression of melanoma by epigenetic and miR221/-222-dependent mechanisms. SCD5 restored expression significantly reduced melanoma malignancy, in human A375M melanoma and in murine 4T1 mammary carcinoma cell lines, mainly by inducing oleic acid. In both cell systems we also evidenced SCD5 effects on tumor microenvironment, through reduced secretion of protumoral protein such as the Secreted Protein Acidic and Rich in Cysteine (SPARC), Collagen IV and Cathepsin B. The net effect of SCD5 action was evidenced by the intracellular acidification (pHe > pHi) and, in turn, by the inhibition of the vesicular trafficking across plasma membranes. This acidification also depends on SCD5-induced reduction of the C2 subunit of the proton pump vacuolar H+-ATPase. Supplementation of oleic acid was per se able to mimic SCD5 enforced expression by reducing the protumoral matrix protein secretion. Our data support a role for SCD5 and its enzymatic product, oleic acid, in protection against malignancy, offering an explanation for the beneficial Mediterranean diet. Furthermore, SCD5 appears to functionally connect tumor cells and the surrounding stroma, with consequences on tumor spread and eventually resistance to treatment.