title: 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.
authors: Department of Haematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors: Maria
authors: M
authors: Bellenghi
authors: Department of Haematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors: Rossella
authors: R
authors: Puglisi
authors: Department of Haematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors: Francesca
authors: F
authors: Pedini
authors: Department of Haematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors: Alessandra
authors: A
authors: De Feo
authors: Department of Haematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors: Federica
authors: F
authors: Felicetti
authors: Department of Haematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors: Lisabianca
authors: L
authors: Bottero
authors: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors: Sabina
authors: S
authors: Sangaletti
authors: Department of Haematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors: Maria Cristina
authors: MC
authors: Errico
authors: Department of Haematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors: Marina
authors: M
authors: Petrini
authors: Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Rome, Italy.
authors: Cinzia
authors: C
authors: Gesumundo
authors: Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Rome, Italy.
authors: Massimo
authors: M
authors: Denaro
authors: Department of Haematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors: Nadia
authors: N
authors: Felli
authors: Department of Haematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors: Luca
authors: L
authors: Pasquini
authors: Department of Health Sciences, University of Palermo, Italy.
authors: Claudio
authors: C
authors: Tripodo
authors: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors: Mario Paolo
authors: MP
authors: Colombo
authors: Department of Haematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors: Alessandra
authors: A
authors: Carè
authors: Department of Haematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors: Gianfranco
authors: G
authors: Mattia
mesh_terms: D002401:Cathepsin B / Q000378:metabolism*; D045744:Cell Line, Tumor; D018450:Disease Progression; D015536:Down-Regulation; D005227:Fatty Acids / Q000032:analysis / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006863:Hydrogen-Ion Concentration; D042541:Intracellular Space / Q000378:metabolism; D008544:Melanocytes / Q000378:metabolism / Q000473:pathology; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D019301:Oleic Acid / Q000032:analysis / Q000378:metabolism*; D015676:Osteonectin / Q000378:metabolism*; D013230:Stearoyl-CoA Desaturase / Q000378:metabolism*
chemical_list: D005227:Fatty Acids; D015676:Osteonectin; C577241:SPARC protein, human; D019301:Oleic Acid; C502659:SCD5 protein, human; D013230:Stearoyl-CoA Desaturase; D002401:Cathepsin B
keywords: SCD5; SPARC; cathepsin B; intracellular acidity; melanoma; oleic acid