title: β-elemene inhibited expression of DNA methyltransferase 1 through activation of ERK1/2 and AMPKα signalling pathways in human lung cancer cells: the role of Sp1.
abstract: β-elemene, a compound derived from Rhizoma zedoariae, is a promising new plant-derived drug with broad-spectrum anticancer activity. However, the underlying mechanism by which this agent inhibits human lung cancer cell growth has not been well elucidated. In this study, we showed that β-elemene inhibits human non-small cell lung carcinoma (NSCLC) cell growth, and increased phosphorylation of ERK1/2, Akt and AMPKα. Moreover, β-elemene inhibited expression of DNA methyltransferase 1 (DNMT1), which was not observed in the presence of the specific inhibitors of ERK (PD98059) or AMPK (compound C). Overexpression of DNMT1 reversed the effect of β-elemene on cell growth. Interestingly, metformin not only reversed the effect of β-elemene on phosphorylation of Akt but also strengthened the β-elemene-reduced DNMT1. In addition, β-elemene suppressed Sp1 protein expression, which was eliminated by either ERK1/2 or AMPK inhibitor. Conversely, overexpression of Sp1 antagonized the effect of β-elemene on DNMT1 protein expression and cell growth. Taken together, our results show that β-elemene inhibits NSCLC cell growth via ERK1/2- and AMPKα-mediated inhibition of transcription factor Sp1, followed by reduction in DNMT1 protein expression. Metformin augments the effect of β-elemene by blockade of Akt signalling and additively inhibition of DNMT1 protein expression. The reciprocal ERK1/2 and AMPKα signalling pathways contribute to the overall responses of β-elemene. This study reveals a potential novel mechanism by which β-elemene inhibits growth of NSCLC cells.
authors.affiliation: Laboratory of Tumor Biology, The second Clinical Medical Collage, University of Guangzhou Traditional Chinese Medicine, Guangdong Province, China.
authors.forename: ShunYu
authors.initials: S
authors.lastname: Zhao
authors.forename: Jingjing
authors.initials: J
authors.lastname: Wu
authors.forename: Fang
authors.initials: F
authors.lastname: Zheng
authors.forename: Qing
authors.initials: Q
authors.lastname: Tang
authors.forename: LiJun
authors.initials: L
authors.lastname: Yang
authors.forename: Liuning
authors.initials: L
authors.lastname: Li
authors.forename: WanYin
authors.initials: W
authors.lastname: Wu
authors.forename: Swei Sunny
authors.initials: SS
authors.lastname: Hann
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000096:biosynthesis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008687:Metformin / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D012717:Sesquiterpenes / Q000494:pharmacology*; D016329:Sp1 Transcription Factor / Q000378:metabolism
chemical_list: D005419:Flavonoids; D034741:RNA, Small Interfering; D012717:Sesquiterpenes; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human; C445979:beta-elemene; D008687:Metformin; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D055372:AMP-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: AMPKα; ERK1/2; NSCLC; Sp1, DNMT1; β-elemene