Within the complex network ofintracellular signals that control cell properties and fate, ceramide has been recognized as a crucial lipid second messenger with anti-proliferative and pro-apoptotic activities.Our preliminary data indicated that 70% of head and neck (H&N) tumors have up-regulated acid ceramidase (AC) expression compared with normal tissue, suggesting unscheduled ceramide metabolism is operative during tumor progression.AC is the central regulator of the balance of the cellular levels of ceramide, sphingosine, and S 1 P, and is integral in determining cell growth or death.In this study, we examined the role of AC and its impact on cell proliferation in H&N cancers.SCC1, 14A, and 22, three independent H&N cancer cell lines with differing levels of AC, were examined and their proliferative capacity were measured.As demonstrated by MTS assay, cell lines characterized with higher AC expression by Western blotting exhibited greater proliferative capability.Dccreased ceramide levels were seen in 14A consistent with its higher endogenous AC level and greater cell growth.Moreover, cell lines generated from metastatic H&N tumor tissues had higher AC levels compared with cell lines generated from primary H&N tumors isolated from the same patient.