Role of Sphingolipids in Multiple Myeloma Progression, Drug Resistance, and Their Potential as Therapeutic Targets

Abstract

Multiple myeloma (MM) is an incapacitating hematological malignancy characterized by accumulation of cancerous plasma cells in the bone marrow (BM) and production of an abnormal monoclonal protein (M-protein). The BM microenvironment has a key role in myeloma development by facilitating the growth of the aberrant plasma cells, which eventually interfere with the homeostasis of the bone cells, exacerbating osteolysis and inhibiting osteoblast differentiation. Recent recognition that metabolic reprograming has a major role in tumor growth and adaptation to specific changes in the microenvironmental niche have led to consideration of the role of sphingolipids and the enzymes that control their biosynthesis and degradation as critical mediators of cancer since these bioactive lipids have been directly linked to the control of cell growth, proliferation, and apoptosis, among other cellular functions. In this review, we present the recent progress of the research investigating the biological implications of sphingolipid metabolism alterations in the regulation of myeloma development and its progression from the pre-malignant stage and discuss the roles of sphingolipids in in MM migration and adhesion, survival and proliferation, as well as angiogenesis and invasion. We introduce the current knowledge regarding the role of sphingolipids as mediators of the immune response and drug-resistance in MM and tackle the new developments suggesting the manipulation of the sphingolipid network as a novel therapeutic direction for MM.

Identification prognostic features related to sphingolipid metabolism and experimental validation of TRIM47 in hepatocellular carcinoma

“…Sphingolipid metabolism is involved in the drugresistance process of cancer cells [41]. Ceramide/S1P rheostat is involved in cell survival, carcinogenesis, and drug sensitivity [42].…”

The emerging roles of sphingosine 1-phosphate and SphK1 in cancer resistance: a promising therapeutic target

“…In multiple myeloma cells, activation of ASM by targeting 67-kDa laminin receptors (67LR) disrupts lipid rafts and suppresses receptor tyrosine kinase (RTK) activation. Multiple myeloma cells have much higher levels of SphK1, a negative regulator of ceramide accumulation with anti-apoptotic effects [ 219 ].…”

Lipid metabolic vulnerabilities of multiple myeloma

“…Ceramides represent a crossroad for the production of other sphingolipids with different, even opposite activities [ 112 ]. The synthesis of sphingomyelin and a vast range of complex glycosphingolipids takes place from ceramide, which occurs mainly in the Golgi.…”

“…Noteworthy, S1P has been reported to regulate hematopoietic progenitor cell lineage and plasma cell localization in the BM [ 117 ]. The work by Petrusca et al highlights S1P as fundamental to send pro-tumor signals by increasing levels of the Growth Factor Independence 1 (GFI1) transcription factor, which consequently leads to increased growth and viability of MM cells, making MM cell resistant to bortezomib-induced cell death and also promoting osteoclastogenesis [ 112 ].…”

“…Regarding the possible link of sphingolipids with drug resistance, it has been reported that sphingomyelin synthesis is associated with the onset of PI resistance in MM cells [ 78 ]. Accordingly, the SMS inhibitor D609 determined a greater cytotoxic effect in cells resistant to the bortezomib and carfilzomib compared to sensitive cells, suggesting a possible dependence of PI resistant cells on sphingomyelin [ 112 ].…”