Biochemistry and cell biology of sphingolipid metabolizing enzymes and their role in cancer and sensitivity to anticancer drugs.
Resistance to anticancer drugs is a major problem in cancer chemotherapy. Studies from our lab over the past 12 years have established that sphingolipids are key regulators in determining sensitivity to chemotherapeutic drugs and other cellular stresses. In particular we have studied the roles of sphingosine-1-phosphate (S-1-P) lysase and sphingosine kinase, which are responsible for the degradation and synthesis of S-1-P, respectively. The work has focused on sensitivity to the commonly used anti-cancer drug cisplatin. We showed that over-expression of sphingosine kinase increases resistance of cells to cisplatin while overexpression of the S-1-P lyase results in increased sensitivity. Moreover, pharmacological inhibition of sphingosine kinase increases sensitivity to cisplatin, which suggests that this could be a useful therapeutic tool in increasing sensitivity to cisplatin.
We have also investigated the role of the family of ceramide synthases, and shown that they each have unique roles in determining sensitivity to cisplatin. The expression of one of them, CerS1, causes an increase in sensitivity and counteracts the increase in resistance caused by the expression of sphingosine kinase, confirming the idea that ceramide and S-1-P act antagonistically. Interestingly, the studies showed that sphingolipids do not modulate sensitivity to all chemotherapeutic agents. Further work has shown that the p38 kinase is required for sphingolipid modulation of chemosensitivity.
Because the levels of sphingolipids are ultimately controlled by the enzymes that synthesize and degrade them, we have studied the cell biology and biochemistry of these enzymes. We have shown that the CerS1 enzyme is regulated by ubiquitination and proteasomal degradation in response to a variety of stresses including chemotherapeutic agents. Neither the CerS4 nor CerS5 enzymes are regulated in this manner. p38 and PKC work antagonistically to regulate the stress induced turnover of CerS1. CerS1 also shows a unique intracellular localization in response to stress. Following stress, CerS1 translocates to from the endoplasimic reticulum to the Golgi apparatus. This translocation is also modulated by p38 and PKC and remarkably requires proteasomal dependent cleavage, and only the C-terminal half of the molecule appears to be translocated to the Golgi apparatus. We are working on determining the function of this translocation as well as the details of the mechanism by which PKC regulates these processes.
Overall, the sphingolipid metabolizing enzymes continue to be an attractive target for cancer therapy, and a fascinating problem in cell biology.
Sridevi, P., Alexander, H., Laviad, E.L., Min, J., Mesika, A., Hannink, M., Futerman, A.H., Alexander, S. (2010) Stress-induced ER to Golgi translocation of ceramide synthase 1 is dependent on proteasomal processing. Exp. Cell Res., 316: 78-91. Epub. October 2, 2009.
Sridevi, P., Alexander, H., Laviad, E.L., Pewzner-Jung, Y., Hannink, M., Futerman, A.H., Alexander, S. (2009) Ceramide synthase 1 is regulated by proteasomal mediated turnover. Biochem. Biophys. Acta, 1793: 1218-1227. Epub. April 22, 2009.
Van Driessche, N., Alexander, H., Min, J., Kuspa, A., Alexander, S., and Shaulsky, G. (2007) Global transcriptional responses to cisplatin in Dictyostelium discoideum identify potential drug targets. Proc Natl Acad Sci USA 104: 15406-15411.
Min, J., Mesika, A., Sivaguru, M., Van Veldhoven, P.P., Alexander, H., Futerman, A.H., and Alexander, S. (2007) (Dihydro)ceramide Synthase 1-regulated sensitivity to cisplatin is associated with the activation of p38 MAP kinase and is abrogated by sphingosine kinase 1. Mol Cancer Res 5: 801-812. (COVER ARTICLE)
Williams, R.S., Boeckeler, K., Graf, R., Muller-Taubenberger, A., Li, Z., Isberg, R.R., Wessels, D., Soll, D.R., Alexander, H., and Alexander, S. (2006). Towards a molecular understanding of human diseases using Dictyostelium discoideum. Trends Mol Med 12: 415-424. Epub. August 4, 2006.
Alexander, S., Min, J., and Alexander, H. (2006). Dictyostelium discoideum to human cells: pharmacogenetic studies demonstrate a role for sphingolipids in chemoresistance. Biochim Biophys Acta 1760: 301-309. Epub. December 22, 2005.
Min, J., Van Veldhoven, P.P., Zhang, L., Hanigan, M.H., Alexander, H., and Alexander, S. (2005b). Sphingosine-1-phosphate lyase regulates sensitivity of human cells to select chemotherapy drugs in a p38-dependent manner. Mol Cancer Res 3: 287-296.
Min, J., Traynor, D., Stegner, A.L., Zhang, L., Hanigan, M.H., Alexander, H., and Alexander, S. (2005a). Sphingosine kinase regulates the sensitivity of Dictyostelium discoideum cells to the anticancer drug cisplatin. Eukaryot Cell 4: 178-189.
Min, J., Stegner, A.L., Alexander, H., and Alexander, S. (2004). Overexpression of sphingosine-1-phosphate lyase or inhibition of sphingosine kinase in Dictyostelium discoideum results in a selective increase in sensitivity to platinum-based chemotherapy drugs. Eukaryot Cell 3: 795-805.