Evaluation of Acid Ceramidase Overexpression-Induced Activation of the Oncogenic Akt Pathway in Prostate Cancer

Prostate cancer is a leading cause of cancer and cancer-related mortality in males in the United States. Acid ceramidase is frequently overexpressed in prostate cancer and catalyzes the deacylation of proapoptotic ceramide into sphingosine. Sphingosine is converted by sphingosine kinases into sphingosine 1-phosphate, which promotes numerous pro-cancer phenotypes. Due to the frequent overexpression of acid ceramidase in prostate cancer and its net cancer promoting signaling effects achieved by reducing ceramide and generating sphingosine 1-phosphate, the impact of acid ceramidase, and the lipid profiles it alters, on prostate cancer cell signaling were studied. Here we report the activation of the oncogenic PI3K/Akt signaling pathway when acid ceramidase is overexpressed both in human prostate tissue and in prostate cancer cell lines. This effect was found to depend on sphingosine kinase 1; potentially reflecting increased accessibility of sphingosine kinase 1 to lysosome-derived sphingosine. Surprisingly, we found that S1P receptor 2 mediates acid ceramidase-induced Akt activation, which challenges the prevailing view in the literature that suggests predominantly tumor suppressive functions for S1P receptor 2. Functionally, acid ceramidase overexpressing cells were found to be resistant to cytotoxic chemotherapies, but profoundly sensitive to inhibition of PI3K or Akt in proliferation assays and soft agar colony formation, suggesting acid ceramidase overexpressing cells become dependent on Akt signaling for their oncogenic phenotypes. The tumor suppressor PTEN classically antagonizes PI3K-mediated activation of Akt, however emerging evidence suggests that nuclear PTEN is also critically important in suppressing cancer. Thus, mechanisms mediating nucleocytoplasmic shuttling of PTEN are of great interest.
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