Modulating glycosphingolipid metabolism and autophagy improves outcomes in pre-clinical models of myeloma bone disease

Abstract

Patients with multiple myeloma, an incurable malignancy of plasma cells, frequently develop osteolytic bone lesions that severely impact quality of life and clinical outcomes. Eliglustat, a U.S. Food and Drug Administration-approved glucosylceramide synthase inhibitor, reduced osteoclast-driven bone loss in preclinical in vivo models of myeloma. In combination with zoledronic acid, a bisphosphonate that treats myeloma bone disease, eliglustat provided further protection from bone loss. Autophagic degradation of TRAF3, a key step for osteoclast differentiation, was inhibited by eliglustat as evidenced by TRAF3 lysosomal and cytoplasmic accumulation. Eliglustat blocked autophagy by altering glycosphingolipid composition whilst restoration of missing glycosphingolipids rescued autophagy markers and TRAF3 degradation thus restoring osteoclastogenesis in bone marrow cells from myeloma patients. This work delineates both the mechanism by which glucosylceramide synthase inhibition prevents autophagic degradation of TRAF3 to reduce osteoclastogenesis as well as highlighting the clinical translational potential of eliglustat for the treatment of myeloma bone disease.

Integrative analysis links autophagy to intrauterine adhesion and establishes autophagy-related circRNA-miRNA-mRNA regulatory network

“…Glycosphingolipid is a bioactive lipid that mediate key processes such as apoptosis and autophagy. Leng et al reported that eliglustat could specifically block the synthesis of glycosphingolipid and autophagic degradation of TRAF3 to reduce osteoclastogenesis [ 27 ]. Furthermore, other metabolic process including the synthesis of cellular nitrogen compound, lysine [ 28 ] and choline [ 29 ] were also associated with autophagy [ 30 ].…”

Lipid metabolic vulnerabilities of multiple myeloma

“…Inhibition of GSL synthesis using NB-DNJ, a selective GCS inhibitor, dramatically inhibited RANKL-induced osteoclastogenesis [ 135 ]. Elegant preclinical studies demonstrated that Eliglustat, an FDA-approved small GSL synthetic inhibitor used for the treatment of Gaucher disease type 1 in adults [ 136 ], was capable to reduce osteoclast-driven bone loss in MGUS and MM models, acting as autophagy inhibitor which prevents TRAF3 degradation through a GLS-dependent mechanism [ 137 ].…”

Autophagy-related mechanisms for treatment of multiple myeloma

“…Glycosphingolipids located outside the cell membrane are important in cell adhesion, cell-cell interactions, and oncogenesis. In MM and MGUS preclinical models, it was shown that Eliglustat can inhibit autophagy through the glycosphingolipid mechanism, thereby maintaining osteoclastogenesis and preventing bone loss [ 169 ] . The tumor burden-reducing effect of the combination of hexokinase-2 inhibitor 3-bromopyruvate and Bortezomib was published [ 87 ] .…”

“…Furthermore, the combination of 3-methyladenine and VEGF inhibitor Bevacizumab in MM cells promoted apoptosis [133] . In a recent study, NVP-BEZ235 was discovered to induce autophagy through the mTOR2-Akt-FOXO3a-BNIP3 signaling pathway in MM cell lines, mouse models, and primary samples [168] . Targeting the PI3K/AKT/mTOR signaling pathway, which is central to cell life and death choices, is a good strategy and a powerful therapeutic option for clinicians.…”