Acid ceramidase (AC) overexpression has been observed in
prostate cancer cell lines and primary
tumors, and contributes to resistance to
chemotherapy and radiation. The consequence of AC overexpression is the ability to convert
ceramide, which is often produced as a proapoptotic response to stress, to
sphingosine, which can then be converted to the prosurvival 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 overexpressing AC also have increased lysosomal density and increased levels of autophagy. Furthermore, pretreatment 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 AC overexpression increases autophagy in
prostate cancer cells, and that increased autophagy enhances resistance to
ceramide.