Role of Sphingosine Kinase in Radiation-Induced Apoptosis of Human Prostate Cancer Cells

摘要

Understanding the biological mechanisms that control cell growth and cell death is a mayor goal in cancer research since it could allow the design of anti-neoplasic therapies to specifically eliminate tumor cells. The effectiveness of radiotherapy and chemotherapy relies in part in their ability to induce a genetic program of cell destruction know as apoptosis. Unfortunately, at present this conventional therapies induce cell death of both normal and cancer cells resulting in undesirable toxic effects. Furthermore, the signaling pathways that lead to apoptosis are often subverted in cancer cells resulting in resistance to radiation or chemotherapy. One mechanism by which cancer cells become resistant to radiation is by disrupting the sphigomyelin pathway that comprises a series of biochemical reactions generating lipid molecules called sphingolipids that are involved in controlling various cellular functions. The sphingolipid metabolites ceramide, sphingosine and sphingosine-l- phosphate (SPP) have recently emerged as a new class messengers that regulate cell growth and apoptosis. While intracellular accumulation of sphingosine or ceramide induces cell death, SPP promotes cell survival. Therefore, our laboratory has proposed that a dynamic balance in the level of intracellular sphingolipids serves as a signal to determine whether a cell survives or dies. In support of this hypothesis it has been found that the sensitivity of specific prostate cancer cell lines to radiation correlates with intracellular ceramide levels and with the activity of sphingosine kinase (SPHK), the enzyme that catalyzes the formation of SPP after adding a phosphate group to sphingosine. I propose to further investigate the role of sphingolipids in radiation-induced apoptosis in prostate cancer.