TY - JOUR
T1 - SCD5-induced oleic acid production reduces melanoma malignancy by intracellular retention of SPARC and cathepsin B
AU - Bellenghi, Maria
AU - Puglisi, Rossella
AU - Pedini, Francesca
AU - De Feo, Alessandra
AU - Felicetti, Federica
AU - Bottero, Lisabianca
AU - Sangaletti, Sabina
AU - Errico, Maria Cristina
AU - Petrini, Marina
AU - Gesumundo, Cinzia
AU - Denaro, Massimo
AU - Felli, Nadia
AU - Pasquini, Luca
AU - Tripodo, Claudio
AU - Colombo, Mario Paolo
AU - Carè, Alessandra
AU - Mattia, Gianfranco
PY - 2015/7/1
Y1 - 2015/7/1
N2 - 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.
AB - 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.
KW - cathepsin B
KW - intracellular acidity
KW - melanoma
KW - oleic acid
KW - SCD5
KW - SPARC
UR - http://www.scopus.com/inward/record.url?scp=84930481899&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84930481899&partnerID=8YFLogxK
U2 - 10.1002/path.4535
DO - 10.1002/path.4535
M3 - Article
C2 - 25802234
AN - SCOPUS:84930481899
VL - 236
SP - 315
EP - 325
JO - Journal of Pathology
JF - Journal of Pathology
SN - 0022-3417
IS - 3
ER -