The relatively recent cloning of nSMase3 means that there has been considerably less study on its functional roles than with the other N-SMases, with no independent confirmation of its activity yet. Thus far, though, acute stimulation of MCF-7 cells with TNF-α was reported to activate nSMase3. Notably, this was impaired by expression of dominant negative FAN suggesting that it acts downstream of FAN in the TNF signaling pathway (Krut et al., 2006). Subsequent study revealed that nSMase3 was transcriptionally induced by TNF-α and DNA damaging agents in colon cancer cells (Corcoran et al., 2008). In contrast, p53, a major genotoxic stress regulator, was observed to downregulate nSMase3 expression. Importantly, nSMase3 expression was found to be decreased in several types of primary tumors suggesting that it may play a role in regulating tumorigenesis.
