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Mammalian sphingosine kinase (SphK) isoenzymes and isoform expression: challenges for SphK as an oncotarget

Diana Hatoum, Nahal Haddadi, Yiguang Lin, Najah T. Nassif and Eileen M. McGowan _

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Oncotarget. 2017; 8:36898-36929. https://doi.org/10.18632/oncotarget.16370

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Abstract

Diana Hatoum1,*, Nahal Haddadi1,*, Yiguang Lin1, Najah T. Nassif1 and Eileen M. McGowan1

1 School of Life Sciences, University of Technology Sydney, Ultimo, Sydney, NSW 2007, Australia

* These authors have contributed equally to this manuscript

Correspondence to:

Eileen M. McGowan, email:

Keywords: sphingosine kinase, isoenzymes, isoforms, cancer, sphingosine-1-phosphate

Received: January 06, 2017 Accepted: March 02, 2017 Published: March 18, 2017

Abstract

The various sphingosine kinase (SphK) isoenzymes (isozymes) and isoforms, key players in normal cellular physiology, are strongly implicated in cancer and other diseases. Mutations in SphKs, that may justify abnormal physiological function, have not been recorded. Nonetheless, there is a large and growing body of evidence demonstrating the contribution of gain or loss of function and the imbalance in the SphK/S1P rheostat to a plethora of pathological conditions including cancer, diabetes and inflammatory diseases. SphK is expressed as two isozymes SphK1 and SphK2, transcribed from genes located on different chromosomes and both isozymes catalyze the phosphorylation of sphingosine to S1P. Expression of each SphK isozyme produces alternately spliced isoforms. In recent years the importance of the contribution of SpK1 expression to treatment resistance in cancer has been highlighted and, additionally, differences in treatment outcome appear to also be dependent upon SphK isoform expression. This review focuses on an exciting emerging area of research involving SphKs functions, expression and subcellular localization, highlighting the complexity of targeting SphK in cancer and also comorbid diseases. This review also covers the SphK isoenzymes and isoforms from a historical perspective, from their first discovery in murine species and then in humans, their role(s) in normal cellular function and in disease processes, to advancement of SphK as an oncotarget.


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