TMEM16A induces MAPK and contributes directly to tumorigenesis and cancer progression

Umamaheswar Duvvuri, Daniel J. Shiwarski, Dong Xiao, Carol Bertrand, Xin Huang, Robert S. Edinger, Jason R. Rock, Brian D. Harfe, Brian J. Henson, Karl Kunzelmann, Rainer Schreiber, Raja S. Seethala, Ann Marie Egloff, Xing Chen, Vivian W. Lui, Jennifer R. Grandis, Susanne M. Gollin

Research output: Contribution to journalArticlepeer-review

205 Scopus citations

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 anchorageindependent 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.

Original languageEnglish (US)
Pages (from-to)3270-3281
Number of pages12
JournalCancer Research
Volume72
Issue number13
DOIs
StatePublished - Jul 1 2012
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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