title: Stabilization of Snail through AKT/GSK-3β signaling pathway is required for TNF-α-induced epithelial-mesenchymal transition in prostate cancer PC3 cells.
abstract: Metastasis induced by chronic inflammation has been considered as a major challenge during cancer therapy. Epithelial-mesenchymal transition (EMT) is associated with cancer invasion and metastasis promoted by pro-inflammatory cytokine TNFα. However, the mechanisms underlying TNFα-induced EMT in prostate cancer cells is not entirely clear. Here we showed that EMT induced by longstanding stimulation with TNFα in prostate cancer PC3 cells is mediated by up-regulation of the transcriptional repressor Snail. TNFα-mediated EMT was characterized by acquiring mesenchymal fusiform morphology, increasing the expression of Vimentin and decreasing the expression of E-cadherin. Exposure to TNFα increased the expression of transcription factor Snail via post-transcriptional regulation process and induced Snail nuclear localization in PC3 cells. Moreover, overexpressed Snail in PC3 cells induced EMT. Conversely, suppressing Snail expression abrogated TNFα-induced EMT, suggesting that Snail plays a crucial role in TNFα-induced EMT in prostate cancer cells. Finally, we showed that TNFα time-dependently activated NF-κB, AKT, ERK, p38 MAPK signaling pathways, and elevated Snail stability by activating AKT pathway that subsequently inhibited GSK-3β activity. Taken together, these results reveal that stabilization of Snail via AKT/GSK-3β signaling pathway is required for TNFα-induced EMT in prostate cancer cells. This study offers a better understanding of TNFα-induced metastasis and provides an effective therapeutic strategy for prostate cancer treatment.
authors.affiliation: Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Rui
authors.initials: R
authors.lastname: Fang
authors.forename: Xian-Feng
authors.initials: XF
authors.lastname: Wang
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.forename: Dan-Yang
authors.initials: DY
authors.lastname: Chen
authors.forename: Binhua
authors.initials: B
authors.lastname: Zhou
authors.forename: Hong-Sheng
authors.initials: HS
authors.lastname: Wang
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; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008297:Male; D011471:Prostatic Neoplasms / Q000473:pathology*; D055550:Protein Stability / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3
keywords: Epithelial–mesenchymal transition; GSK-3β; Prostate cancer; Snail