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Cancer Res. 2012 Jul 1;72(13):3270-81. doi: 10.1158/0008-5472.CAN-12-0475-T. Epub 2012 May 7.

TMEM16A induces MAPK and contributes directly to tumorigenesis and cancer progression.

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  • 1Department of Otolaryngology, University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine and Magee-Women's Research Institute, Pittsburgh, Pennsylvania 15213, USA. duvvuriu@upmc.edu

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.

©2012 AACR.

PMID:
22564524
[PubMed - indexed for MEDLINE]
PMCID:
PMC3694774
Free PMC Article

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