1. TMEM16A Induces MAPK and Contributes Directly to Tumorigenesis and Cancer Progression.
- Author
-
Duvvuri, Umamaheswar, Shiwarski, Daniel J., Dong Xiao, Bertrand, Carol, Xin Huang, Edinger, Robert S., Rock, Jason R., Harfe, Brian D., Henson, Brian J., Kunzelmann, Karl, Schreiber, Rainer, Seethala, Raja S., Egloff, Ann Marie, Xing Chen, Lui, Vivian W., Grandis, Jennifer R., and Gollin, Susanne M.
- Subjects
- *
GENES , *CANCER , *POLYMERASE chain reaction , *CANCER cells , *CYCLINS - 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 , and loss of TMEM16A resulted in inhibition of tumor growth both and in vitro in vitro 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 . Together, our findings provide a in vitro 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. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF