Regulation of Sphingosine Kinase in Prostate Cancer Cells

摘要

Sphingosine kinase 1 (SphK1) and its product sphingosine 1-phosphate have been shown to promote cell growth and inhibit apoptosis of tumor cells (reviewed in 1) . SphK1 has been shown to be responsible for radioresistance of certain prostate cancer cells 2. To better understand SphK1 regulation, we undertook a two-hybrid screen for SphK1-interacting proteins. In the first report period, we focused on one of these interactors, aminoacylase 1. This work will not be discussed as it has been accepted for publication (appendix A) . In this report period we studied a second interacting protein, filamin A. We show that SphK1 physically interacts with both the fragment of filamin found in the two-hybrid screen and full length. Though both C-terminal and full length proteins reduce SphK1 activity measured in vitro, the C-terminal fragment inhibits while the full length potentiates the effects of SphK1 on TNF-alpha signaling and motility. We further demonstrate that filamin is required for ligand-induced motility as well as activation of SphK1. Moreover, siRNA against SphK1 suggests the SphK1-filamin interaction is required for motility, indicating possible anti-metastasis drug targets.