Journal Article

EGFR overexpression induces activation of telomerase via PI3K/AKT-mediated phosphorylation and transcriptional regulation through Hif1-alpha in a cellular model of oral-esophageal carcinogenesis

QUEISSER Angela, HARDER Jan, GOESSEL Gitta, HEEG Steffen, QUANTE Michael, BLUM Hubert E., SCHMIEG Hannah, KUNERT Heike, OPITZ Oliver G., THALER Michaela, HIRT Nina, VON WERDER Alexander, BEIJERSBERGEN Roderick, NAKAGAWA Hiroshi

2011

Overview

Telomerase plays an important role during immortalization and malignant transformation as crucial steps in the development of human cancer. In a cellular model of oral–esophageal carcinogenesis, recapitulating the human disease, immortalization occurred independent of the activation of telomerase but through the recombination‐based alternative lengthening of telomeres (ALT). In this stepwise model, additional overexpression of EGFR led to in vitro transformation and activation of telomerase with homogeneous telomere elongation in already immortalized oral squamous epithelial cells (OKF6‐D1_dnp53). More interestingly, EGFR overexpression activated the PI3K/AKT pathway. This strongly suggested a role for telomerase in tumor progression in addition to just elongating telomeres and inferring an immortalized state. Therefore, we sought to identify the regulatory mechanisms involved in this activation of telomerase and in vitro transformation induced by EGFR. In the present study we demonstrate that telomerase expression and activity are induced through both direct phosphorylation of hTERT by phospho‐AKT as well as PI3K‐dependent transcriptional regulation involving Hif1‐alpha as a key transcription factor. Furthermore, EGFR overexpression enhanced cell cycle progression and proliferation via phosphorylation and translocation of p21. Whereas immortalization was induced by ALT, in vitro transformation was associated with telomerase activation, supporting an additional role for telomerase in tumor progression besides elongating telomeres. (Cancer Sci 2011; 102: 351–360)

• Publisher: Blackwell Publishing Ltd,Blackwell
• Subject: 1-Phosphatidylinositol 3-kinase / Biological and medical sciences / Blotting, Western / Cell Transformation, Neoplastic - genetics / Cell Transformation, Neoplastic - metabolism / Cells, Cultured / Enzyme Activation - physiology / Esophageal Neoplasms - genetics / Esophageal Neoplasms - metabolism / Fluorescent Antibody Technique / Gene Expression / Gene Expression Regulation, Neoplastic - physiology / Humans / Hypoxia-Inducible Factor 1, alpha Subunit - metabolism / Immunoprecipitation / In Situ Hybridization, Fluorescence / Medical sciences / Mouth Neoplasms - genetics / Mouth Neoplasms - metabolism / Otorhinolaryngology. Stomatology / Phosphatidylinositol 3-Kinases - metabolism / Phosphorylation / Proto-Oncogene Proteins c-akt - metabolism / Receptor, Epidermal Growth Factor - biosynthesis / Receptor, Epidermal Growth Factor - genetics / Reverse Transcriptase Polymerase Chain Reaction / Signal Transduction - physiology / Telomerase - metabolism / Transcription, Genetic / Tumors / Upper respiratory tract, upper alimentary tract, paranasal sinuses, salivary glands: diseases, semeiology