title: TMEM16A induces MAPK and contributes directly to tumorigenesis and cancer progression.
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.
authors.affiliation: Department 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
authors.forename: Umamaheswar
authors.initials: U
authors.lastname: Duvvuri
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Shiwarski
authors.forename: Dong
authors.initials: D
authors.lastname: Xiao
authors.forename: Carol
authors.initials: C
authors.lastname: Bertrand
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.forename: Robert S
authors.initials: RS
authors.lastname: Edinger
authors.forename: Jason R
authors.initials: JR
authors.lastname: Rock
authors.forename: Brian D
authors.initials: BD
authors.lastname: Harfe
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Henson
authors.forename: Karl
authors.initials: K
authors.lastname: Kunzelmann
authors.forename: Rainer
authors.initials: R
authors.lastname: Schreiber
authors.forename: Raja S
authors.initials: RS
authors.lastname: Seethala
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Egloff
authors.forename: Xing
authors.initials: X
authors.lastname: Chen
authors.forename: Vivian W
authors.initials: VW
authors.lastname: Lui
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Grandis
authors.forename: Susanne M
authors.initials: SM
authors.lastname: Gollin
mesh_terms: D000818:Animals; D000075369:Anoctamin-1; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018450:Disease Progression; D004789:Enzyme Activation; D004790:Enzyme Induction; D006258:Head and Neck Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C476213:ANO1 protein, human; D000075369:Anoctamin-1; D018118:Chloride Channels; D009363:Neoplasm Proteins; D020928:Mitogen-Activated Protein Kinases