Drug Resistance: The Role of Sphingolipid Metabolism

Abstract

A significant challenge in cancer treatment is the rising problem of drug resistance that reduces the effectiveness of therapeutic strategies. Current knowledge shows that multiple mechanisms play a role in cancer drug resistance. Another mechanism that has gained attention is the alteration in sphingolipid trafficking and the dysregulation of its metabolism, which was reported to cause cancer-associated drug resistance. Sphingolipids are lipids containing sphingosine and have multiple roles, ranging from lipid raft formation, apoptosis, and cell signaling to immune cell trafficking. Recent studies show that in developing cancer cells, altered or dysregulated sphingolipids are associated with drug efflux and promote the survival of cancer cells by bypassing apoptosis. Upregulated levels of the glucosylceramide synthase (GCS), an enzyme that functions in sphingolipid metabolism, lead to the upregulated ABCB1 gene that induces drug efflux from the cancer cells. These bypass mechanisms make drugs that induce apoptosis in tumor cells ineffective. By highlighting the current findings, this review aims to provide a mechanism of drug resistance caused by the dysregulation of glucosylceramide synthase, sphingosine kinase, and acid ceramidase enzymes as possible therapeutic targets to enhance the effectiveness of the currently used chemotherapeutic agents.

Keywords: acid ceramidase; drug resistance; glucosylceramide synthase; sphingolipid metabolism; sphingomyelinase; sphingosine kinase; sphingosine-1-phosphate.

Figure 1

Sphingolipid synthesis pathways. Schematic illustration of sphingolipid synthesis showing that SLs can be formed via de novo synthesis in endoplasmic reticulum through a cascade of enzyme-catalyzed reactions or through the breakdown of glycosylceramides or sphingomyelins in the salvage pathway. Ceramides play a central role in the sphingolipid metabolism and are modified to form more complex sphingolipids. Tumor-suppressing and tumor-promoting functions are indicated with green and red arrows, respectively. Sphingolipids (SLs); GCS, glucosylceramide synthase; SPT, serine palmitoyltransferase; 3-KSR, 3-ketosphinganine reductase; CerS, ceramide synthase; DES, dihydroceramide desaturase; GlcCDase, glucosylceramidase; CERT, ceramide transfer protein; CerK, ceramide kinase; C1PP, ceramide-1-phosphatase; CDase, ceramidase; SMS, sphingomyelin synthase; aSMase, acid sphingomyelinase; SPHK1, sphingosine kinase 1; S1PP, sphingosine-1-phosphatase; SMase, sphingomyelinase.

Figure 2

S1P-mediated signaling pathways. Schematic illustration showing intracellular S1P can be transported via ABC/SPNS2 transporters and bind S1PR1-S1PR5 G-protein coupled receptors and activate several pro-tumorigenic pathways that lead to cellular proliferation, growth and migration. Gi/o activates pro-survival pathways PI3K/Akt or Ras/MAPK/ERK, which leads to increased cell proliferation and growth of the cancer cells, making existing apoptosis-inducing treatment inefficient [31]. S1P can upregulate the production of P-glycoprotein, which actively extrudes cancer-targeted drugs out of the cell, thereby enhancing tumor drug resistance [29]. SPHK activates the JAK/STAT signaling pathway via the S1PR1 receptor in colon cancer cell lines, which induces migration and invasiveness [32].