Duvvuri, Umamaheswar and Shiwarski, Daniel J. and Xiao, Dong and Bertrand, Carol and Huang, Xin and Edinger, Robert S. and Rock, Jason R. and Harfe, Brian D. and Henson, Brian J. and Kunzelmann, Karl and Schreiber, Rainer and Seethala, Raja S. and Egloff, Ann Marie and Chen, Xing and Lui, Vivian W. and Grandis, Jennifer R. and Gollin, Susanne M. (2012) TMEM16A Induces MAPK and Contributes Directly to Tumorigenesis and Cancer Progression. CANCER RESEARCH, 72 (13). pp. 3270-3281. ISSN 0008-5472, 1538-7445
Full text not available from this repository. (Request a copy)Abstract
Frequent gene amplification of the receptor-activated calcium-dependent chloride channel TMEM16A (TAOS2 or ANO1) has been reported in several malignancies. However, its involvement in human tumorigenesis has not been previously studied. Here, we show a functional role for TMEM16A in tumor growth. We found TMEM16A overexpression in 80% of head and neck squamous cell carcinoma (SCCHN), which correlated with decreased overall survival in patients with SCCHN. TMEM16A overexpression significantly promoted anchorage-independent growth in vitro, and loss of TMEM16A resulted in inhibition of tumor growth both in vitro and in vivo. Mechanistically, TMEM16A-induced cancer cell proliferation and tumor growth were accompanied by an increase in extracellular signal-regulated kinase (ERK) 1/2 activation and cyclin D1 induction. Pharmacologic inhibition of MEK/ERK and genetic inactivation of ERK1/2 (using siRNA and dominant-negative constructs) abrogated the growth effect of TMEM16A, indicating a role for mitogen-activated protein kinase (MAPK) activation in TMEM16A-mediated proliferation. In addition, a developmental small-molecule inhibitor of TMEM16A, T16A-inh01 (A01), abrogated tumor cell proliferation in vitro. Together, our findings provide a mechanistic analysis of the tumorigenic properties of TMEM16A, which represents a potentially novel therapeutic target. The development of small-molecule inhibitors against TMEM16A may be clinically relevant for treatment of human cancers, including SCCHN. Cancer Res; 72(13); 3270-81. (C) 2012 AACR.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | SQUAMOUS-CELL CARCINOMA; ACTIVATED CHLORIDE CHANNEL; CA2+-ACTIVATED CL-CHANNELS; TRANSMEMBRANE CONDUCTANCE REGULATOR; GASTROINTESTINAL STROMAL TUMORS; ORAL-CANCER; TRANSCRIPTOME ANALYSIS; INTERSTITIAL-CELLS; EPITHELIAL-CELLS; 11Q13 AMPLICON; |
| Subjects: | 500 Science > 570 Life sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Physiologie Biology, Preclinical Medicine > Institut für Physiologie > Prof. Dr. Karl Kunzelmann |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 11 May 2020 07:05 |
| Last Modified: | 11 May 2020 07:05 |
| URI: | https://pred.uni-regensburg.de/id/eprint/18478 |
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