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

Maria Bellenghi, Rossella Puglisi, Francesca Pedini, Alessandra De Feo, Federica Felicetti, Lisabianca Bottero, Sabina Sangaletti, Maria Cristina Errico, Marina Petrini, Cinzia Gesumundo, Massimo Denaro, Nadia Felli, Luca Pasquini, Claudio Tripodo, Mario Paolo Colombo, Alessandra Carè, Gianfranco Mattia

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)315-325
Number of pages11
JournalJournal of Pathology
Volume236
Issue number3
DOIs
Publication statusPublished - Jul 1 2015

Keywords

  • cathepsin B
  • intracellular acidity
  • melanoma
  • oleic acid
  • SCD5
  • SPARC

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Medicine(all)

Fingerprint Dive into the research topics of 'SCD5-induced oleic acid production reduces melanoma malignancy by intracellular retention of SPARC and cathepsin B'. Together they form a unique fingerprint.

Cite this