TMEM16A Induces MAPK and Contributes Directly to Tumorigenesis and Cancer Progression

被引:284
作者
Duvvuri, Umamaheswar [1 ,8 ]
Shiwarski, Daniel J. [1 ]
Xiao, Dong [1 ]
Bertrand, Carol [2 ]
Huang, Xin [6 ,7 ]
Edinger, Robert S. [5 ]
Rock, Jason R. [11 ]
Harfe, Brian D. [12 ,13 ]
Henson, Brian J. [9 ,10 ]
Kunzelmann, Karl [14 ]
Schreiber, Rainer [14 ]
Seethala, Raja S. [3 ]
Egloff, Ann Marie [1 ]
Chen, Xing [1 ]
Lui, Vivian W. [1 ]
Grandis, Jennifer R. [1 ,4 ]
Gollin, Susanne M. [1 ,3 ,9 ,10 ]
机构
[1] Univ Pittsburgh, Med Ctr, Dept Otolaryngol, Pittsburgh, PA 15213 USA
[2] Univ Pittsburgh, Med Ctr, Dept Cell Biol & Physiol, Pittsburgh, PA 15213 USA
[3] Univ Pittsburgh, Med Ctr, Dept Pathol, Pittsburgh, PA 15213 USA
[4] Univ Pittsburgh, Med Ctr, Dept Pharmacol & Chem Biol, Pittsburgh, PA 15213 USA
[5] Univ Pittsburgh, Med Ctr, Renal & Electrolyte Div, Pittsburgh, PA 15213 USA
[6] Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA 15213 USA
[7] Univ Pittsburgh, Med Ctr, Magee Womens Res Inst, Pittsburgh, PA 15213 USA
[8] Vet Affairs Pittsburgh Hlth Syst, Pittsburgh, PA USA
[9] Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15213 USA
[10] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA 15213 USA
[11] Duke Univ, Med Ctr, Dept Cell Biol, Durham, NC 27710 USA
[12] Univ Florida, Dept Mol Genet & Microbiol, Gainesville, FL USA
[13] Univ Florida, Genet Inst, Gainesville, FL USA
[14] Univ Regensburg, Dept Physiol, Regensburg, Germany
关键词
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;
D O I
10.1158/0008-5472.CAN-12-0475-T
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:3270 / 3281
页数:12
相关论文
共 49 条
[1]   Exome Sequencing of Head and Neck Squamous Cell Carcinoma Reveals Inactivating Mutations in NOTCH1 [J].
Agrawal, Nishant ;
Frederick, Mitchell J. ;
Pickering, Curtis R. ;
Bettegowda, Chetan ;
Chang, Kyle ;
Li, Ryan J. ;
Fakhry, Carole ;
Xie, Tong-Xin ;
Zhang, Jiexin ;
Wang, Jing ;
Zhang, Nianxiang ;
El-Naggar, Adel K. ;
Jasser, Samar A. ;
Weinstein, John N. ;
Trevino, Lisa ;
Drummond, Jennifer A. ;
Muzny, Donna M. ;
Wu, Yuanqing ;
Wood, Laura D. ;
Hruban, Ralph H. ;
Westra, William H. ;
Koch, Wayne M. ;
Califano, Joseph A. ;
Gibbs, Richard A. ;
Sidransky, David ;
Vogelstein, Bert ;
Velculescu, Victor E. ;
Papadopoulos, Nickolas ;
Wheeler, David A. ;
Kinzler, Kenneth W. ;
Myers, Jeffrey N. .
SCIENCE, 2011, 333 (6046) :1154-1157
[2]  
AKERVALL JA, 1995, CANCER, V76, P853, DOI 10.1002/1097-0142(19950901)76:5<853::AID-CNCR2820760520>3.0.CO
[3]  
2-6
[4]   TMEM16 Proteins Produce Volume-regulated Chloride Currents That Are Reduced in Mice Lacking TMEM16A [J].
Almaca, Joana ;
Tian, Yuemin ;
Aldehni, Fadi ;
Ousingsawat, Jiraporn ;
Kongsuphol, Patthara ;
Rock, Jason R. ;
Harfe, Brian D. ;
Schreiber, Rainer ;
Kunzelmann, Karl .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2009, 284 (42) :28571-28578
[5]   ANO1 amplification and expression in HNSCC with a high propensity for future distant metastasis and its functions in HNSCC cell lines [J].
Ayoub, C. ;
Wasylyk, C. ;
Li, Y. ;
Thomas, E. ;
Marisa, L. ;
Robe, A. ;
Roux, M. ;
Abecassis, J. ;
de Reynies, A. ;
Wasylyk, B. .
BRITISH JOURNAL OF CANCER, 2010, 103 (05) :715-726
[6]   TMEM16A, a membrane protein associated with calcium-dependent chloride channel activity [J].
Caputo, Antonella ;
Caci, Emanuela ;
Ferrera, Loretta ;
Pedemonte, Nicoletta ;
Barsanti, Cristina ;
Sondo, Elvira ;
Pfeffer, Ulrich ;
Ravazzolo, Roberto ;
Zegarra-Moran, Olga ;
Galietta, Luis J. V. .
SCIENCE, 2008, 322 (5901) :590-594
[7]   Head and neck squamous cell carcinoma transcriptome analysis by comprehensive validated differential display [J].
Carles, A ;
Millon, R ;
Cromer, A ;
Ganguli, G ;
Lemaire, F ;
Young, J ;
Wasylyk, C ;
Muller, D ;
Schultz, I ;
Rabouel, Y ;
Dembélé, D ;
Zhao, C ;
Marchal, P ;
Ducray, C ;
Bracco, L ;
Abecassis, J ;
Poch, O ;
Wasylyk, B .
ONCOGENE, 2006, 25 (12) :1821-1831
[8]   Prognostic impact of array-based genomic profiles in esophageal squamous cell cancer [J].
Carneiro, Ana ;
Isinger, Anna ;
Karlsson, Anna ;
Johansson, Jan ;
Jonsson, Goeran ;
Bendahl, Paer-Ola ;
Falkenback, Dan ;
Halvarsson, Britta ;
Nilbert, Mef .
BMC CANCER, 2008, 8 (1)
[9]   Mitochondrially localized ERK2 regulates mitophagy and autophagic cell stress [J].
Dagda, Ruben K. ;
Zhu, Jianhui ;
Kulich, Scott M. ;
Chu, Charleen T. .
AUTOPHAGY, 2008, 4 (06) :770-782
[10]   Tumor suppression by a proapoptotic calcium-activated chloride channel in mammary epithelium [J].
Elble, RC ;
Pauli, BU .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (44) :40510-40517