Head and neck cancer is one of the most morbid human malignancies with an overall poor prognosis and severely compromised quality of life. As a result, there is significant interest in developing adjuvant therapies to augment currently available treatment protocols. Curcumin has been found to possess anti-cancer activities via its effect on a variety of biological pathways. In this study, we showed that curcumin inhibits head and neck cancer cell growth through reduction of PGE(2) receptor EP4 gene expression. Blockade of AMP-dependent kinase (AMPK), and p38 MAPK by either chemical inhibitors or siRNAs antagonized the inhibitory effect of curcumin on EP4 expression, which was reversed by metformin, an activator of AMPK Curcumin induced PGC-1 alpha protein that was blocked by compound C and SB239063. Silencing of PGC-1 alpha reversed the effect of curcumin on EP4 protein. Overexpression of EP4 overcame the effect of curcumin on head and neck cancer cell growth. In addition, curcumin reduced Sp1 protein. Overexpression of Sp1 resisted the inhibitory effect of curcumin on EP4 promoter activity and protein expression. Interestingly, overexpression of PGC-1 alpha further enhanced the inhibitory effect of curcumin on Sp1 protein expression that was blocked by SB239063. In conclusion, this study shows that curcumin inhibits EP4 gene expression dependent of AMPK alpha and p38 MAPK activation, this leads to reduction of Sp1 protein and binding to specific area in the EP4 gene promoter. The cross talks of AMPK alpha and p38 MAPK signaling, the kinase-mediated PGC-1 alpha expression and reciprocity of PGC-1 alpha and Sp1 enhance this process. This ultimately results in inhibition of head and neck cancer cell proliferation. (C) 2013 Elsevier Inc. All rights reserved.