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Sphingosine kinases signalling in carcinogenesis.

Gabriella Marfe, Giovanna Mirone, Arvind Shukla

  • 1Department of Biochemistry and Biophysics, Second University of Naples, Via De Crecchio 7, Naples 80138, Italy. gabmarfe@alice.it.

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Sphingosine kinases (Sphk1 and 2) produce sphingosine-1-phosphate (S1P), crucial in cancer. SphK1 overexpression drives cancer and TKI resistance, while SphK2’s role needs further study.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Sphingosine kinases (Sphk1 and 2) regulate sphingosine-1-phosphate (S1P) production, a key mediator in cancer development.
  • SphK1 is frequently overexpressed in tumors, contributing to cancer pathogenesis and resistance to tyrosine kinase inhibitors (TKIs).
  • The role of SphK2 in pathological conditions, particularly in promoting apoptosis and inhibiting cell growth, requires further elucidation.

Purpose of the Study:

  • To investigate the role of sphingosine kinases (Sphk1 and 2) and their product, sphingosine-1-phosphate (S1P), in cancer development.
  • To understand the contribution of SphK1 overexpression to cancer pathogenesis and TKI resistance.
  • To explore the potential roles of SphK2 in cellular processes relevant to cancer.

Main Methods:

  • Analysis of sphingosine kinase activity and S1P production.
  • Investigating the involvement of receptor tyrosine kinases (RTKs) in Sphk1 activation.
  • Examining the signaling pathways mediated by S1P receptors and their interaction with RTKs.

Main Results:

  • SphK1 activation by growth factor-induced RTKs leads to sphingosine phosphorylation.
  • SphK1-produced S1P engages its five receptors, influencing cellular processes.
  • A positive-feedback loop involving S1P receptors and RTKs amplifies signaling.

Conclusions:

  • SphK1 plays a significant role in cancer progression and TKI resistance.
  • Understanding SphK1 activation mechanisms is crucial for developing effective pharmacological inhibitors.
  • Further research into SphK2's functions may reveal new therapeutic targets.