Abstract
Sphingosine kinases (SPHKs) are conserved lipid enzymes that catalyze the formation of sphingosine-1-phosphate (S1P) through ATP-dependent phosphorylation of sphingosine. Two distinct SPHK isoforms, namely SPHK1 and SPHK2, have been identified to date, and the former has been implicated for its oncogenic roles in cancer development and progression. While SPHK1 signaling axis has been extensively studied in non-stem breast cancer cells, recent evidence has emerged to suggest a role of SPHK1 in regulating cancer stem cells (CSCs). With the clinical implications of CSCs in disease relapse and metastasis, it is believed that therapeutic approaches that can eradicate both non-stem cancer cells and CSCs could be a key to cancer cure. In this review, we first explore the oncogenic functions of sphingosine kinase 1 in human cancers and summarize current research findings of SPHK1 signaling with a focus on breast cancer. We also discuss the therapeutic potentials and perspectives of targeting SPHK1 signaling in breast cancer and cancer stem cells. We aim to offer new insights and inspire future studies looking further into the regulatory functions of SPHK1 in CSC-driven tumorigenesis, uncovering novel therapeutic avenues of using SPHK1-targeted therapy in the treatment of CSC-enriched refractory cancers.
Highlights
Sphingolipids are one of the main classes of bioactive lipid molecules found in eukaryotic cells
Despite some eagerly highlight the oncogenic roles of SPHK1/S1P axis in breast cancer stem cells (CSCs) based on existing mechanisms established from non-stem cancer cells, specific investigations in the context of breast CSCs, are generally lacking nowadays
With the chemotactic functions of S1P in the immunomodulation and microenvironmental regulation, it is tempting to speculate that SPHK1/S1P axis may aid to regulate the antitumor functions of various immune cells, assist immunosurveillance of breast CSCs, and create a conducive tumor microenvironment (TME) for CSC propagation and maintenance
Summary
Sphingolipids are one of the main classes of bioactive lipid molecules found in eukaryotic cells. Ceramide is deacylated into sphingosine by ceramidase, and sphingosine can be further phosphorylated to form S1P by sphingosine kinase (SPHK); in turn, S1P can either be irreversibly degraded by S1P lyase, or dephosphorylated to sphingosine via S1P phosphatase, followed by re-acylation back to ceramide by ceramide synthase (Hannun and Obeid, 2018; Ogretmen, 2018). Such interconversions are rapid and mediated through compartment-specific processes. The distinct roles and downstream targets of these bioactive sphingolipids are highly context- and cell type-dependent
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