hTERT mediates norepinephrine-induced Slug expression and ovarian cancer aggressiveness

• Published in: Oncogene Vol. 34; no. 26; pp. 3402 - 3412
• Main Authors: Choi, M J, Cho, K H, Lee, S, Bae, Y J, Jeong, K J, Rha, S Y, Choi, E J, Park, J H, Kim, J M, Lee, J-S, Mills, G B, Lee, H Y
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2015; Nature Publishing Group
• Subjects: 14; 14/19; 38; 38/39; 631/67/322; 96/106; 96/109; 96/95; Adrenergic receptors; Animals; Apoptosis; c-Myc protein; Catecholamines; Cell Biology; Development and progression; Ectopic expression; Female; Gene Expression Regulation, Neoplastic - drug effects; Genetic aspects; Genetic transcription; Health aspects; Hormones; Human Genetics; Humans; Hypoxia-inducible factors; Internal Medicine; Kinases; Lung cancer; Medicine; Medicine & Public Health; Mesenchyme; Metastases; Metastasis; Mice; Mice, Nude; Myc protein; Neoplasm Invasiveness; Neoplasm Metastasis; Norepinephrine; Norepinephrine - pharmacology; Oncology; original-article; Ovarian cancer; Ovarian Neoplasms - genetics; Ovarian Neoplasms - pathology; Properties; Protein kinase A; Proteins; RNA-directed DNA polymerase; Snail Family Transcription Factors; Stress; Telomerase; Telomerase - physiology; Telomerase reverse transcriptase; Therapeutic applications; Transcription; Transcription Factors - genetics; Transferases; Tumor Cells, Cultured; Up-Regulation - drug effects
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2014.270

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.