Estrogen induction of telomerase activity through regulation of the mitogen-activated protein kinase (MAPK) dependent pathway in human endometrial cancer cells

• Published in: PloS one Vol. 8; no. 2; p. e55730
• Main Authors: Zhou, Chunxiao, Steplowski, Tara A, Dickens, Hallum K, Malloy, Kimberly M, Gehrig, Paola A, Boggess, John F, Bae-Jump, Victoria L
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 07.02.2013; Public Library of Science (PLoS)
• Subjects: 17β-Estradiol; Biology; Butadienes - pharmacology; Cancer; Cancer cells; Carcinogenesis; Carcinogens; Cell Line, Tumor; Cloning; Deoxyribonucleic acid; DNA; Endometrial cancer; Endometrial Neoplasms - genetics; Endometrial Neoplasms - metabolism; Endometrium; Enzyme Activation - drug effects; Estradiol; Estradiol - pharmacology; Estrogen receptors; Estrogens; Estrogens - pharmacology; Exposure; Extracellular signal-regulated kinase; Female; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Gynecology; Hormones; Humans; Infection; Kinases; Luciferase; MAP kinase; Medicine; Menstruation; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Mitogen-Activated Protein Kinases - metabolism; Mitogens; Nitriles - pharmacology; Obstetrics; Oncology; Phenols (Class of compounds); Phosphorylation; Promoter Regions, Genetic; Protein kinase; Protein kinases; Proteins; Regulatory sequences; RNA; RNA Interference; RNA, Messenger - genetics; RNA, Messenger - metabolism; Sex hormones; Signal Transduction - drug effects; siRNA; Telomerase; Telomerase - genetics; Telomerase - metabolism; Telomerase reverse transcriptase; Transcription factors; Transfection; Uterine cancer; North Carolina; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0055730

Given that prolonged exposure to estrogen and increased telomerase activity are associated with endometrial carcinogenesis, our objective was to evaluate the interaction between the MAPK pathway and estrogen induction of telomerase activity in endometrial cancer cells. Estradiol (E2) induced telomerase activity and hTERT mRNA expression in the estrogen receptor (ER)-α positive, Ishikawa endometrial cancer cell line. UO126, a highly selective inhibitor of MEK1/MEK2, inhibited telomerase activity and hTERT mRNA expression induced by E2. Similar results were also found after transfection with ERK 1/2-specific siRNA. Treatment with E2 resulted in rapid phosphorylation of p44/42 MAPK and increased MAPK activity which was abolished by UO126. The hTERT promoter contains two estrogen response elements (EREs), and luciferase assays demonstrate that these EREs are activated by E2. Exposure to UO126 or ERK 1/2-specific siRNA in combination with E2 counteracted the stimulatory effect of E2 on luciferase activity from these EREs. These findings suggest that E2-induction of telomerase activity is mediated via the MAPK pathway in human endometrial cancer cells.