More recently, nSMase2 has been implicated in cancer pathogenesis. A study of primary osteoblasts found that treatment with conditioned medium from a prostate cancer cell line (PC-3) significantly reduced nSMase2 expression (Schulze et al., 2009). As prostate cancer primarily metastasizes to bone, this study suggested that nSMase2 may play a role in cancer cell migration and osteoclast activation. Moreover, a number of mutations in the nSMase2 gene, smpd3, were identified in cancer (Kim et al., 2008) with nSMase2 mutations found in 5% of acute myeloid leukemias and 6% of 131 acute lymphoid leukemias. Notably, two of the reported leukemia mutations led to decreased stability of nSMase2 or mislocalization of the protein within the cell. Finally, a homozygous deletion of the smpd3 gene was found in a murine osteosarcoma model. Taken together, these results have begun to suggest a functional role for the nSMase2/ceramide pathway in the regulation of tumorigenesis. However, considerable further studies are required to address this fully.
