The Opposing Contribution of SMS1 and SMS2 to Glioma Progression and Their Value in the Therapeutic Response to 2OHOA

Abstract

Background: 2-Hydroxyoleic acid (2OHOA) is particularly active against glioblastoma multiforme (GBM) and successfully finished a phase I/IIA trial in patients with glioma and other advanced solid tumors. However, its mechanism of action is not fully known. Methods: The relationship between SMS1 and SMS2 expressions (mRNA) and overall survival in 329 glioma patients was investigated, and so was the correlation between SMS expression and 2OHOA’s efficacy. The opposing role of SMS isoforms in 2OHOA’s mechanism of action and in GBM cell growth, differentiation and death, was studied overexpressing or silencing them in human GBM cells. Results: Patients with high-SMS1 plus low-SMS2 expression had a 5-year survival ~10-fold higher than patients with low-SMS1 plus high-SMS2 expression. SMS1 and SMS2 also had opposing effect on GBM cell survival and 2OHOA’s IC50 correlated with basal SMS1 levels and treatment induced changes in SMS1/SMS2 ratio. SMSs expression disparately affected 2OHOA’s cancer cell proliferation, differentiation, ER-stress and autophagy. Conclusions: SMS1 and SMS2 showed opposite associations with glioma patient survival, glioma cell growth and response to 2OHOA treatment. SMSs signature could constitute a valuable prognostic biomarker, with high SMS1 and low SMS2 being a better disease prognosis. Additionally, low basal SMS1 mRNA levels predict positive response to 2OHOA.

Deficiency of sphingomyelin synthase 2 prolongs survival by the inhibition of lymphoma infiltration through ICAM‐1 reduction

“…Fernández-García et al recently demonstrated through database analyses that glioblastoma multiforme patients with low SMS2 expression showed prolonged median survival compared patients with high SMS2 expression. 49 However, we could not find an association between SMS2 and ICAM-1 with poor prognostic lymphoma and infiltration from databases. One reason may be that these databases focus on the characterization of cancer cells but not on host cells associated with them.…”

Membrane Lipid Composition: Effect on Membrane and Organelle Structure, Function and Compartmentalization and Therapeutic Avenues

“…Oncology. The basis of developing MLT in oncology comes from the finding that membrane lipid composition might work as a switch allowing or compromising propagation of proliferation signals received at the PM in tumor cells [196,207]. Many molecules have been developed since the discovery membrane-altering mechanism of action of doxorubicin [199].…”

Ceramide/Sphingomyelin Rheostat Regulated by Sphingomyelin Synthases and Chronic Diseases in Murine Models

“…EL4 injection increased ICAM-1 in the liver of WT mice but not in SMS2-KO mice. Moreover, a recent database analysis by Fernández-García et al 132 has demonstrated that SMS2 expression was low in glioblastoma multiforme patients, and was associated with prolonged median survival. Therefore, SM reduction by SMS2 inhibition could be a therapeutic target for the prevention of not only malignant lymphoma infiltration but also other cancers including glioblastoma.…”