title: Inhibition of integrin-linked kinase expression by emodin through crosstalk of AMPKα and ERK1/2 signaling and reciprocal interplay of Sp1 and c-Jun.
abstract: Despite the anti-cancer effect of emodin observed in several cancers, the underlying molecular mechanism remains to be elucidated. In this study, we showed that emodin-inhibited NSCLC cell growth and increased phosphorylation of AMPKα and ERK1/2. In addition, emodin-inhibited ILK protein expression. The overexpression of ILK reversed the effect of emodin on cell growth inhibition. Furthermore, the blockade of AMPK by compound C abrogated, while metformin, an activator of AMPK, strengthened the effect of emodin on the inhibition of ILK expression. Interestingly, the inhibitor of MAPK extracellular signaling-regulated kinase (ERK) kinase (MEK)/ERK1/2 (PD98059) attenuated emodin-induced phosphorylation of AMPKα. Moreover, emodin reduced the protein expression of Sp1 and AP-1 subunit c-Jun. Exogenous expression of Sp1 and c-Jun diminished emodin-reduced ILK protein expression. Emodin suppressed ILK promoter activity, which was not observed in cells overexpression of Sp1 and treated with compound C. Intriguingly, exogenous expression of c-Jun overcame the emodin-inhibited Sp1 protein expression. Collectively, our results demonstrate that emodin inhibits ILK expression through AMPKα-mediated reduction of Sp1 and c-Jun. Metformin enhances the effects of emodin. Exogenous expression of Sp1 and c-Jun resists emodin-inhibited ILK promoter activity and protein expression. In addition, the overexpression of c-Jun diminishes emodin-induced AMPKα signaling. Thus, the crosstalk of AMPKα and MEK/ERK1/2 signaling and the reciprocal interaction between Sp1 and c-Jun proteins contribute to the overall responses of emodin. This novel signaling axis may be a therapeutic potential for prevention and treatment of NSCLC.
authors.affiliation: Laboratory of Tumor Biology, Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical Medical College, University of Guangzhou Traditional Chinese Medicine, Guangzhou, Guangdong Province 510120, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Tang
authors.affiliation: Laboratory of Tumor Biology, Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical Medical College, University of Guangzhou Traditional Chinese Medicine, Guangzhou, Guangdong Province 510120, China.
authors.forename: Shunyu
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Laboratory of Tumor Biology, Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical Medical College, University of Guangzhou Traditional Chinese Medicine, Guangzhou, Guangdong Province 510120, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Wu
authors.affiliation: Laboratory of Tumor Biology, Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical Medical College, University of Guangzhou Traditional Chinese Medicine, Guangzhou, Guangdong Province 510120, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Zheng
authors.affiliation: Laboratory of Tumor Biology, Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical Medical College, University of Guangzhou Traditional Chinese Medicine, Guangzhou, Guangdong Province 510120, China.
authors.forename: LiJun
authors.initials: L
authors.lastname: Yang
authors.affiliation: Laboratory of Tumor Biology, Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical Medical College, University of Guangzhou Traditional Chinese Medicine, Guangzhou, Guangdong Province 510120, China.
authors.forename: JingHeng
authors.initials: J
authors.lastname: Hu
authors.affiliation: Laboratory of Tumor Biology, Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical Medical College, University of Guangzhou Traditional Chinese Medicine, Guangzhou, Guangdong Province 510120, China. Electronic address: swhan20010@live.com.
authors.forename: Swei Sunny
authors.initials: SS
authors.lastname: Hann
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004642:Emodin / Q000633:toxicity*; D006801:Humans; D007004:Hypoglycemic Agents / Q000633:toxicity; D008687:Metformin / Q000633:toxicity; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic; D047428:Protein Kinase Inhibitors / Q000633:toxicity*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D000099200:Scaffold Protein ILK
chemical_list: D055372:AMP-Activated Protein Kinases; D004642:Emodin; D007004:Hypoglycemic Agents; D008687:Metformin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D016755:Proto-Oncogene Proteins c-jun; D016329:Sp1 Transcription Factor; D000099200:Scaffold Protein ILK
keywords: AMPKα; Emodin; ILK; NSCLC; Sp1; c-Jun