title: Snail regulated by PKC/GSK-3β pathway is crucial for EGF-induced epithelial-mesenchymal transition (EMT) of cancer cells.
abstract: Cancer metastasis is considered a major challenge in cancer therapy. Recently, epidermal growth factor (EGF)/epidermal growth factor receptor (EGFR) signaling has been shown to induce epithelial-mesenchymal transition (EMT) and thereby to promote cancer metastasis. However, the underlying mechanism has not been fully elucidated. We demonstrate that EGF can induce EMT in human prostate and lung cancer cells and thus promote invasion and migration. EGF-induced EMT has been characterized by the cells acquiring mesenchymal spindle-like morphology and increasing their expression of N-cadherin and fibronectin, with a concomitant decrease of E-cadherin. Both protein and mRNA expression of transcription factor Snail rapidly increases after EGF treatment. The knockdown of Snail significantly attenuates EGF-induced EMT, suggesting that Snail is crucial for this process. To determine the way that Snail is accumulated, we demonstrate (1) that EGF promotes the stability of Snail via inhibiting the activity of glycogen synthase kinase 3 beta (GSK-3β), (2) that protein kinase C (PKC) rather than the phosphatidylinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway is responsible for GSK-3β inhibition and (3) that GSK-3β inhibition promotes the transcription of Snail. Taken together, these results reveal that the PKC/GSK-3β signaling pathway controls both the stability and transcription of Snail, which is crucial for EMT induced by EGF in PC-3 and A549 cells. Our study suggests a novel signaling pathway for Snail regulation and provides a better understanding of growth-factor-induced tumor EMT and metastasis.
authors.affiliation: Department of Microbial and Biochemical Pharmacy School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, 510006, People's Republic of China.
authors.forename: Zong-cai
authors.initials: ZC
authors.lastname: Liu
authors.forename: Xiao-hui
authors.initials: XH
authors.lastname: Chen
authors.forename: Hai-xing
authors.initials: HX
authors.lastname: Song
authors.forename: Hong-sheng
authors.initials: HS
authors.lastname: Wang
authors.forename: Ge
authors.initials: G
authors.lastname: Zhang
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Dan-yang
authors.initials: DY
authors.lastname: Chen
authors.forename: Rui
authors.initials: R
authors.lastname: Fang
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.forename: Shao-hui
authors.initials: SH
authors.lastname: Cai
authors.forename: Jun
authors.initials: J
authors.lastname: Du
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D011493:Protein Kinase C / Q000378:metabolism*; D055550:Protein Stability / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D004815:Epidermal Growth Factor; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D011493:Protein Kinase C; D038362:Glycogen Synthase Kinase 3