Abstract
Sphingosine kinase (SphK) is a lipid enzyme that maintains cellular lipid homeostasis. Two SphK isozymes, SphK1 and SphK2, are expressed from different chromosomes and several variant isoforms are expressed from each of the isozymes, allowing for the multi-faceted biological diversity of SphK activity. Historically, SphK1 is mainly associated with oncogenicity, however in reality, both SphK1 and SphK2 isozymes possess oncogenic properties and are recognized therapeutic targets. The absence of mutations of SphK in various cancer types has led to the theory that cancer cells develop a dependency on SphK signaling (hyper-SphK signaling) or “non-oncogenic addiction”. Here we discuss additional theories of SphK cellular mislocation and aberrant “dicing and splicing” as contributors to cancer cell biology and as key determinants of the success or failure of SphK/S1P (sphingosine 1 phosphate) based therapeutics.
Highlights
The theory that shifts in lipid metabolism drive oncogenesis and tumor recurrence, whereby cancer cells display alterations in fundamental cellular metabolism, is gaining credence [1,2,3,4]
Albeit this C4 sequence has the greatest diversity between the Sphingosine kinase 1 (SphK1) and Sphingosine kinase 2 (SphK2) isozymes, the domain responsible for sphingosine binding, suggesting this domain is responsible for preferred sphingosine substrate specificity [94,96]
There is a strong, indisputable, causal association between adverse Sphingosine kinase (SphK)/sphingosine 1 phosphate (S1P) signaling and cancer, to date there have been no reports of SphK/S1P receptors (S1PRs) mutations linked to cancer development and it has been suggested that cancer cells develop a dependence on SphK cellular signaling, referred to as “non-oncogene addiction” [86]
Summary
The theory that shifts in lipid metabolism drive oncogenesis and tumor recurrence, whereby cancer cells display alterations in fundamental cellular metabolism, is gaining credence [1,2,3,4]. Key cellular roles for SphK/S1P include the promotion of cell survival and proliferation, prevention of apoptosis, maintenance of vascularization and stimulation of angiogenesis for tissue regeneration in tissue damage, metabolic rewiring, and metabolic stability [5,6,7,8,9] While these actions are important for cellular function, undesirable consequences of these cellular functions, when not restrained, underpin the mechanisms of oncogenesis, including uncontrolled cell division, pro-inflammatory responses, cell invasion and metastasis (Figure 1) [3,10]. (increase) in S1P expression, through overexpression of SphK activity, illustrated by dashed lines to is causally associated with cancer development, inflammation, angiogenesis and metastasis [1]. Importance of Isoenzymes (Isozymes) and Variant Isoforms in the Future of Cancer Treatment
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