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Sphingosine kinase-1 as a chemotherapy sensor in prostate adenocarcinoma cell and mouse models
Dimitri Pchejetski1, Muriel Golzio, Elisabeth Bonhoure
1Inserm, U466, Toulouse, France.
Abstract:
Systemic chemotherapy was considered of modest efficacy in prostate cancer until the recent introduction of taxanes. We took advantage of the known differential effect of camptothecin and docetaxel on human PC-3 and LNCaP prostate cancer cells to determine their effect on sphingosine kinase-1 (SphK1) activity and subsequent ceramide/sphingosine 1-phosphate (S1P) balance in relation with cell survival. In vitro, docetaxel and camptothecin induced strong inhibition of SphK1 and elevation of the ceramide/S1P ratio only in cell lines sensitive to these drugs. SphK1 overexpression in both cell lines impaired the efficacy of chemotherapy by decreasing the ceramide/S1P ratio. Alternatively, silencing SphK1 by RNA interference or pharmacologic inhibition induced apoptosis coupled with ceramide elevation and loss of S1P. The differential effect of both chemotherapeutics was confirmed in an orthotopic PC-3/green fluorescent protein model established in nude mice. Docetaxel induced a stronger SphK1 inhibition and ceramide/S1P ratio elevation than camptothecin. This was accompanied by a smaller tumor volume and the reduced occurrence and number of metastases. SphK1-overexpressing PC-3 cells implanted in animals developed remarkably larger tumors and resistance to docetaxel treatment. These results provide the first in vivo demonstration of SphK1 as a sensor of chemotherapy.
Insights
Chemotherapy efficacy in prostate cancer improved with taxanes. Sphingosine kinase-1 (SphK1) inhibition by chemotherapy alters the ceramide/sphingosine 1-phosphate (S1P) balance, impacting cancer cell survival and metastasis.
Area of Science:
- Oncology
- Biochemistry
- Molecular Biology
Background:
- Systemic chemotherapy had limited efficacy in prostate cancer prior to taxane development.
- Taxanes exhibit differential effects on prostate cancer cell lines, influencing sphingosine kinase-1 (SphK1) activity.
- The balance between ceramide and sphingosine 1-phosphate (S1P) is crucial for cell survival.
Purpose of the Study:
- To investigate the impact of camptothecin and docetaxel on SphK1 activity and the ceramide/S1P balance in prostate cancer cells.
- To determine the role of SphK1 in mediating chemotherapy response and cell survival.
- To validate the in vivo effects of SphK1 modulation on tumor growth and metastasis.
Main Methods:
- In vitro studies using PC-3 and LNCaP prostate cancer cell lines.
- Manipulation of SphK1 activity via overexpression, RNA interference, and pharmacologic inhibition.
- Orthotopic xenograft mouse model (PC-3/GFP) to assess in vivo drug efficacy and metastasis.
- Measurement of SphK1 activity and ceramide/S1P levels.
Main Results:
- Docetaxel and camptothecin inhibited SphK1 and increased the ceramide/S1P ratio in sensitive cell lines.
- SphK1 overexpression reduced chemotherapy efficacy by decreasing the ceramide/S1P ratio.
- SphK1 inhibition induced apoptosis, increased ceramide, and decreased S1P.
- In vivo, docetaxel showed greater SphK1 inhibition and ceramide/S1P elevation than camptothecin, reducing tumor volume and metastasis.
- SphK1-overexpressing tumors exhibited increased growth and docetaxel resistance.
Conclusions:
- SphK1 activity is a key determinant of chemotherapy response in prostate cancer.
- Modulating the ceramide/S1P balance via SphK1 inhibition enhances chemotherapy efficacy.
- SphK1 acts as a sensor of chemotherapy, influencing tumor progression and metastasis in vivo.
