The
tumor suppressor PTEN is now understood to regulate cellular processes at the cytoplasmic membrane, where it classically regulates PI3K signaling, as well as in the nucleus where multiple roles in controlling cell cycle and
genome stability have been elucidated. Mechanisms that dictate nuclear import and, less extensively, nuclear export of PTEN have been described, however the relevance of these processes in disease states, particularly
cancer, remain largely unknown. We investigated the impact of
acid ceramidase on the nuclear-cytoplasmic trafficking of PTEN. Immunohistochemical analysis of a human prostate tissue microarray revealed that nuclear PTEN was lost in patients whose
tumors had elevated
acid ceramidase. We found that
acid ceramidase promotes a reduction in nuclear PTEN that is dependent upon
sphingosine 1-phosphate-mediated activation of Akt. We were further able to show that
sphingosine 1-phosphate promotes formation of a complex between Crm1 and PTEN, and that
leptomycin B prevents
acid ceramidase and
sphingosine 1-phosphate mediated loss of nuclear PTEN, suggesting an active
exportin-mediated event. To investigate whether the
tumor promoting aspects of
acid ceramidase in
prostate cancer depend upon its ability to export PTEN from the nucleus, we used enforced nuclear expression of PTEN to study
docetaxel-induced apoptosis and cell killing, proliferation, and xenoengraftment. Interestingly, while
acid ceramidase was able to protect cells expressing wild type PTEN from
docetaxel, promote proliferation and xenoengraftment,
acid ceramidase had no impact in cells expressing PTEN-NLS. These findings suggest that
acid ceramidase, through
sphingosine 1-phosphate, promotes nuclear export of PTEN as a means of promoting
tumor formation, cell proliferation, and resistance to
therapy.