title: hTERT mediates norepinephrine-induced Slug expression and ovarian cancer aggressiveness.
abstract: Stress hormones have been implicated in both tumor initiation and progression. Human telomerase reverse transcriptase (hTERT) is overexpressed in cancer cells and associated with malignant tumor progression and poor outcome. We thus sought to determine whether the stress hormone norepinephrine (NE) could induce hTERT expression and subsequently ovarian cancer progression. Unexpectedly, NE induced hTERT transcript and protein expression, and subsequently ovarian cancer cell invasion. Pharmacologic inhibition of β2-adrenergic receptor 2 and protein kinase A, as well as silencing of hypoxia-inducible factor-1α and c-Myc expression, profoundly attenuated NE-induced hTERT expression. Strikingly, stimulation of the cells with NE or ectopic expression of hTERT induced expression of Slug, ovarian cancer cell epithelial-mesenchymal transition (EMT) and invasion. Silencing of hTERT expression abrogated NE-induced ovarian cancer cell invasion, EMT and Slug expression. In addition, silencing of Slug expression significantly inhibited NE- and hTERT-induced ovarian cancer cell EMT and invasion. Moreover, continuous exposure to NE was sufficient to enhance in vivo hTERT expression and metastasis of ovarian cancer cells to the lung. Finally, we provide evidence that hTERT links Src to Slug expression in NE-induced ovarian cancer EMT and metastasis. We thus demonstrate a novel role of hTERT in stress hormone-induced ovarian cancer aggressiveness through inducing Slug, providing novel biomarkers and potential therapeutic targets for ovarian cancer.
authors.affiliation: Department of Pharmacology, Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon, Korea.
authors.forename: M J
authors.initials: MJ
authors.lastname: Choi
authors.affiliation: Department of Pharmacology, Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon, Korea.
authors.forename: K H
authors.initials: KH
authors.lastname: Cho
authors.affiliation: Department of Biochemistry, Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon, Korea.
authors.forename: S
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon, Korea.
authors.forename: Y J
authors.initials: YJ
authors.lastname: Bae
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: K J
authors.initials: KJ
authors.lastname: Jeong
authors.affiliation: Yonsei Cancer Research Institute, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: S Y
authors.initials: SY
authors.lastname: Rha
authors.affiliation: Department of Optometry, College of Medical Science, Konyang University, Daejeon, Korea.
authors.forename: E J
authors.initials: EJ
authors.lastname: Choi
authors.affiliation: Department of Biochemistry, Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon, Korea.
authors.forename: J H
authors.initials: JH
authors.lastname: Park
authors.affiliation: Cancer Research Institute, Regional Cancer Center and Infection Signaling Network Research Center, Chungnam National University School of Medicine, Daejeon, Korea.
authors.forename: J M
authors.initials: JM
authors.lastname: Kim
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: J-S
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: G B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: 1] Department of Pharmacology, Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon, Korea [2] Yonsei Cancer Research Institute, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: H Y
authors.initials: HY
authors.lastname: Lee
mesh_terms: D000818:Animals; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009638:Norepinephrine / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology*; D000071250:Snail Family Transcription Factors; D019098:Telomerase / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C000604407:SNAI1 protein, human; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C509186:TERT protein, human; D019098:Telomerase; D009638:Norepinephrine