Title:Sphingosine Kinases Signalling in Carcinogenesis
Volume: 15
Issue: 4
Author(s): Gabriella Marfe, Giovanna Mirone, Arvind Shukla and Carla Di Stefano
Affiliation:
Keywords:
Cancer, receptor tyrosine kinases (RTKs), sphingosine kinase 1 (SphK1), sphingolipids, sphingosine 1-phosphate
(S1P), tyrosine kinase inibitors (TKIs).
Abstract: Sphingosine kinases (Sphk1 and 2) regulate the prodution of sphingosine-1-phosphate
(S1P), that is key molecule in cancer development. SphK1, which is commonly overexpressed in
malignant tumours, significantly contributes to the pathogenesis of various types of cancer as well as
to resistance to different Tyrosine Kinase inibitors (TKIs). Even, SphK2 may promote apoptosis and
inhibit cell growth but its role has not yet been fully understood in pathologic conditions. Different growth factorsinduced
activation of receptor tyrosine kinases (RTKs) results in production of Sphk1 which catalyzes the
phosphorylation of sphingosine. Such enzyme, in turn, is involved in many cellular processes by its five receptors. These
are able to transactivate RTKs through amplification of a positive-feedback signaling loop. In conclusion, development of
pharmacological inhibitors of SphK1 has been limited by the lack of completely understanding of the enzymatic
activation mechanisms of SphK1.
