Autophagy is increased in prostate cancer cells over-expressing acid ceramidase and enhances resistance to C(6)-ceramide

Acid ceramidase (AC) over-expression has been observed in prostate cancer cell lines and primary tumors, and contributes to resistance to chemotherapy and radiation. The consequence of AC over-expression is the ability to convert ceramide, which is often produced as a pro-apoptotic response to stress, to sphingosine, which can then be converted to the pro-survival molecule sphingosine-1-phosphate. In addition to their ability to metabolize ceramide produced in response to stress, we show here that prostate cancer cell lines over-expressing acid ceramidase also have increased lysosomal density and increased levels of autophagy. Furthermore, pre-treatment with 3-methyladenine restores sensitivity of these cells to treatment with C(6)-ceramide. We also observed increased expression of the lysosomal stabilizing protein KIF5B and increased sensitivity to the lysosomotropic agent LCL385. Thus, we conclude that acid ceramidase over-expression increases autophagy in prostate cancer cells, and that increased autophagy enhances resistance to ceramide.