TY  - JOUR
A1  - Barcelo-Coblijn, Gwendolyn
A1  - Laura Martin, Maria
A1  - de Almeida, Rodrigo F. M.
A1  - Antonia Noguera-Salva, Maria
A1  - Marcilla-Etxenike, Amaia
A1  - Guardiola-Serrano, Francisca
A1  - Lueth, Anja
A1  - Kleuser, Burkhard
A1  - Halver, John E.
A1  - Escriba, Pablo V.
T1  - Sphingomyelin and sphingomyelin synthase (SMS) in the malignant transformation of glioma cells and in 2-hydroxyoleic acid therapy
JF  - Proceedings of the National Academy of Sciences of the United States of America
N2  - The mechanism of action of 2-hydroxyoleic acid (2OHOA), a potent antitumor compound, has not yet been fully elucidated. Here, we show that human cancer cells have markedly lower levels of sphingomyelin (SM) than nontumor (MRC-5) cells. In this context, 2OHOA treatment strongly augments SM mass (4.6-fold), restoring the levels found in MRC-5 cells, while a loss of phosphatidylethanolamine and phosphatidylcholine is observed (57 and 30%, respectively). The increased SM mass was due to a rapid and highly specific activation of SM synthases (SMS). This effect appeared to be specific against cancer cells as it did not affect nontumor MRC-5 cells. Therefore, low SM levels are associated with the tumorigenic transformation that produces cancer cells. SM accumulation occurred at the plasma membrane and caused an increase in membrane global order and lipid raft packing in model membranes. These modifications would account for the observed alteration by 2OHOA in the localization of proteins involved in cell apoptosis (Fas receptor) or differentiation (Ras). Importantly, SMS inhibition by D609 diminished 2OHOA effect on cell cycle. Therefore, we propose that the regulation of SMS activity in tumor cells is a critical upstream event in 2OHOA antitumor mechanism, which also explains its specificity for cancer cells, its potency, and the lack of undesired side effects. Finally, the specific activation of SMS explains the ability of this compound to trigger cell cycle arrest, cell differentiation, and autophagy or apoptosis in cancer cells.
KW  - anticancer
KW  - membrane-lipid therapy
KW  - lung cancer
KW  - membrane lipids
Y1  - 2011
U6  - https://doi.org/10.1073/pnas.1115484108
SN  - 0027-8424
VL  - 108
IS  - 49
SP  - 19569
EP  - 19574
PB  - National Acad. of Sciences
CY  - Washington
ER  -