title: Targeting EP4 by curcumin through cross talks of AMP-dependent kinase alpha and p38 mitogen-activated protein kinase signaling: the role of PGC-1α and Sp1.
abstract: 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 PGE2 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-1α protein that was blocked by compound C and SB239063. Silencing of PGC-1α 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-1α 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 AMPKα 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 AMPKα and p38 MAPK signaling, the kinase-mediated PGC-1α expression and reciprocity of PGC-1α and Sp1 enhance this process. This ultimately results in inhibition of head and neck cancer cell proliferation.
authors.affiliation: Laboratory of Tumor Molecular Biology and Targeted Therapies, University of Guangzhou Traditional Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong Province, 510120 China. Electronic address: swhan2010@live.com.
authors.forename: Swei Sunny
authors.initials: SS
authors.lastname: Hann
authors.forename: Jianping
authors.initials: J
authors.lastname: Chen
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Wang
authors.forename: Jingjing
authors.initials: J
authors.lastname: Wu
authors.forename: Fang
authors.initials: F
authors.lastname: Zheng
authors.forename: Shunyu
authors.initials: S
authors.lastname: Zhao
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003474:Curcumin / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008687:Metformin / Q000494:pharmacology; D058990:Molecular Targeted Therapy; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D034622:RNA Interference; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D058309:Receptors, Prostaglandin E, EP4 Subtype; D014157:Transcription Factors; D008687:Metformin; D048051:p38 Mitogen-Activated Protein Kinases; D000263:Adenylate Kinase; D003474:Curcumin
keywords: AMPK/p38 MAPK; Curcumin; EP4; Head and neck cancer cells; PGC-1α; Sp1