SCD5‐induced oleic acid production reduces melanoma malignancy by intracellular retention of SPARC and cathepsin B

Abstract

A proper balance between saturated and unsaturated fatty acids (FAs) is required for maintaining cell homeostasis. The increased demand of FAs to assemble the plasma membranes of continuously dividing cancer cells might unbalance this ratio and critically affect tumour outgrowth. We unveiled the role of the stearoyl-CoA desaturase SCD5 in converting saturated FAs into mono-unsaturated FAs during melanoma progression. SCD5 is down-regulated in advanced melanoma and its restored expression significantly reduced melanoma malignancy, both in vitro and in vivo, through a mechanism governing the secretion of extracellular matrix proteins, such as secreted protein acidic and rich in cysteine (SPARC) and collagen IV and of their proteases, such as cathepsin B. Enforced expression of SCD5 or supplementation of its enzymatic product, oleic acid, reduced the intracellular pH (pHe > pHi) and, in turn, vesicular trafficking across plasma membranes as well as melanoma dissemination. This intracellular acidification appears also to depend on SCD5-induced reduction of the C2 subunit of the vacuolar H(+) -ATPase, a proton pump whose inhibition changes the secretion profile of cancer cells. 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 tumour cells and the surrounding stroma toward modification of the tumour microenvironment, with consequences on tumour spread and resistance to treatment.

Sterculic Acid: The Mechanisms of Action beyond Stearoyl-CoA Desaturase Inhibition and Therapeutic Opportunities in Human Diseases

“…Its expression is downregulated during tumor progression and related to the epithelial-mesenchymal transition reverted process [13]. SCD5 expression is associated with the reduction of intracellular pH, vesicle movement, and pro-tumoral protein secretion [19]. It has also been described that miR-221 and miR-222 have a negative feedback connection to SCD5 expression [13].…”

The Stearoyl-CoA Desaturase-1 (Desat1) in Drosophila cooperated with Myc to Induce Autophagy and Growth, a Potential New Link to Tumor Survival

“…The growing evidence for a prominent role of lipids in tumor growth, together with the fact that human SCD-1, and more recently also SCD-5, have been found expressed and associated with the malignancy of the disease [31,42], prompted us to analyze if the expression of c-Myc correlates with increased levels of SCD-1 or SCD-5 in tumors with higher prognosis of tumorigenesis. Since SCD-1 protein is increased in prostate tumors [31], we decided to analyze whether c-Myc and SCD-1 proteins are co-expressed in histological tumor samples from patients and control tissues using immunofluorescence assays.…”

Identification of differentially expressed genes and functional annotations associated with metastases of the uveal melanoma

“…Cell homeostasis is highly associated with the balance between saturated and unsaturated FAs. The continuously dividing tumor cells need a large amount of FAs to assemble their plasma membranes; this may disrupt the ratio and assist tumor growth . However, previous studies have suggested that stearoyl‐CoA desaturase 5 (SCD5) reduces the aggressiveness of UVM .…”

“…33 However, previous studies have suggested that stearoyl-CoA desaturase 5 (SCD5) reduces the aggressiveness of UVM. 33,34 Further research is needed to verify this.…”