Radiation resistance in a subset of prostate
tumors remains a challenge to
prostate cancer radiotherapy. The current study on the effects of radiation on
prostate cancer cells reveals that radiation programs an unpredicted resistance mechanism by upregulating
acid ceramidase (AC). Irradiated cells demonstrated limited changes of
ceramide levels while elevating levels of
sphingosine and
sphingosine-1-phosphate. By genetically downregulating AC with
small interfering RNA (
siRNA), we observed radiosensitization of cells using clonogenic and cytotoxicity assays. Conversely, AC overexpression further decreased sensitivity to radiation. We also observed that radiation-induced AC upregulation was sufficient to create cross-resistance to
chemotherapy as demonstrated by decreased sensitivity to
Taxol and C(6)
ceramide compared to controls. Lower levels of
caspase 3/7 activity were detected in cells pretreated with radiation, also indicating increased resistance. Finally, utilization of the small molecule AC inhibitor,
LCL385, sensitized PPC-1 cells to radiation and significantly decreased
tumor xenograft growth. These data suggest a new mechanism of
cancer cell resistance to radiation, through upregulation of AC that is, in part, mediated by application of the
therapy itself. An improved understanding of
radiotherapy and the application of combination
therapy achieved in this study offer new opportunities for the modulation of radiation effects in the treatment of
cancer.