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Mammalian sphingosine kinase (SphK) isoenzymes and isoform expression: challenges for SphK as an oncotarget
Diana Hatoum1, Nahal Haddadi1, Yiguang Lin1
1School of Life Sciences, University of Technology Sydney, Ultimo, Sydney, NSW 2007, Australia.
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.
Insights
Sphingosine kinases (SphK) are crucial in cell function and implicated in diseases like cancer. Targeting SphK isoenzymes and isoforms offers potential therapeutic strategies for various pathological conditions.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Sphingosine kinases (SphK) are key regulators of cellular physiology.
- SphK isoenzymes (SphK1 and SphK2) and their isoforms play critical roles in various diseases, including cancer, diabetes, and inflammatory conditions.
- While mutations are not recorded, dysregulation of SphK activity and the sphingosine-1-phosphate (S1P) rheostat contribute to pathological processes.
Purpose of the Study:
- To review the functions, expression, and subcellular localization of SphK isoenzymes and isoforms.
- To highlight the complexity of targeting SphK in cancer and comorbid diseases.
- To provide a historical perspective on SphK research, from discovery to its advancement as an oncotarget.
Main Methods:
- Literature review and synthesis of existing research on SphK isoenzymes and isoforms.
- Analysis of the role of SphK in normal cellular function and disease pathogenesis.
- Exploration of SphK as a therapeutic target in oncology.
Main Results:
- SphK isoenzymes (SphK1 and SphK2) catalyze the phosphorylation of sphingosine to S1P, with distinct isoforms arising from alternative splicing.
- SphK expression is linked to treatment resistance in cancer, and outcomes can depend on specific SphK isoform expression.
- Imbalances in the SphK/S1P pathway are implicated in numerous diseases beyond cancer.
Conclusions:
- SphK isoenzymes and isoforms represent a complex but promising area for therapeutic intervention in cancer and other diseases.
- Understanding the intricate roles and localization of SphK is crucial for developing effective targeted therapies.
- SphK has evolved from a basic research subject to a significant oncotarget with potential for treating multiple pathological conditions.