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Sphingosine kinase inhibition to sensitize hormone‐resistant prostate cancer cells to docetaxel
Author(s) -
Pshezhetskiy Dmitry
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.519.1
Subject(s) - docetaxel , prostate cancer , lncap , medicine , sphingosine kinase 1 , cancer , chemotherapy , cancer research , oncology , apoptosis , sphingosine , prostate , cancer cell , biology , sphingosine 1 phosphate , biochemistry , receptor
It has recently been shown that docetaxel chemotherapy is effective in prolonging life in patients with prostate cancer. We have investigated potential ways of increasing the effectiveness of chemotherapy in this disease. We have previously reported that sphingosine kinase‐1 (SK1) inhibition is a key step in docetaxel‐induced apoptosis in the PC‐3 prostate cancer cell line (Pchejetski et al, Cancer Res 2005) and that pharmacological SK1 inhibition is chemosensitizing in the docetaxel‐resistant prostate cancer LNCaP cell line (Pchejetski et al, Mol Cancer Ther, 2008). In this current study we have addressed the mechanism of docetaxel‐induced apoptosis of PC‐3 cells and identified SK1‐dependent and ‐independent components. We have shown that SK1 inhibition by docetaxel is a two‐step process involving an initial loss of enzyme activity followed by a decrease in SK1 gene expression. We have demonstrated that both pharmacological and siRNA‐mediated SK1 inhibition leads to a four‐fold decrease in the docetaxel dose required to cause prostate cancer cell apoptosis. Overall we have identified a mechanism of docetaxel‐induced SK1‐mediated prostate cancer cell apoptosis. This work points to potential ways of increasing the effectiveness of chemotherapy for prostate cancer by SK1 inhibition.