Hann Swei Sunny, Chen Jianping, Wang Zhiyu, Wu Jingjing, Zheng Fang, Zhao Shunyu
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.
Cell Signal. 2013 Dec;25(12):2566-74. doi: 10.1016/j.cellsig.2013.08.020. Epub 2013 Aug 30.
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.
头颈癌是最具致死性的人类恶性肿瘤之一，总体预后较差，生活质量严重受损。因此，人们对开发辅助疗法以增强现有治疗方案有着浓厚兴趣。姜黄素已被发现通过其对多种生物途径的作用而具有抗癌活性。在本研究中，我们表明姜黄素通过降低前列腺素E2受体EP4基因表达来抑制头颈癌细胞生长。用化学抑制剂或小干扰RNA阻断AMP依赖激酶（AMPK）和p38丝裂原活化蛋白激酶（p38 MAPK）可拮抗姜黄素对EP4表达的抑制作用，而AMPK激活剂二甲双胍可逆转这种作用。姜黄素诱导PGC-1α蛋白表达，这一过程被化合物C和SB239063阻断。沉默PGC-1α可逆转姜黄素对EP4蛋白的作用。过表达EP4可克服姜黄素对头颈癌细胞生长的影响。此外，姜黄素降低Sp1蛋白水平。过表达Sp1可抵抗姜黄素对EP4启动子活性和蛋白表达的抑制作用。有趣的是，过表达PGC-1α进一步增强了姜黄素对Sp1蛋白表达的抑制作用，而该作用被SB239063阻断。总之，本研究表明姜黄素抑制EP4基因表达依赖于AMPKα和p38 MAPK的激活，这导致Sp1蛋白减少并与EP4基因启动子的特定区域结合。AMPKα和p38 MAPK信号通路的相互作用、激酶介导的PGC-1α表达以及PGC-1α和Sp1的相互作用增强了这一过程。这最终导致头颈癌细胞增殖受到抑制。
