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Cancer Therapy: Preclinical

TMEM16A/ANO1 Inhibits Apoptosis Via Downregulation of Bim Expression

Neal R. Godse, Nayel Khan, Zachary A. Yochum, Roberto Gomez-Casal, Carolyn Kemp, Daniel J. Shiwarski, Raja S. Seethala, Scott Kulich, Mukund Seshadri, Timothy F. Burns and Umamaheswar Duvvuri
Neal R. Godse
University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.Department of Otolaryngology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
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Nayel Khan
Department of Otolaryngology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
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Zachary A. Yochum
University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
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Roberto Gomez-Casal
Department of Otolaryngology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
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Carolyn Kemp
Department of Otolaryngology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
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Daniel J. Shiwarski
Department of Otolaryngology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.VA Pittsburgh Health System, Pittsburgh, Pennsylvania.
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Raja S. Seethala
Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.
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Scott Kulich
Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.
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Mukund Seshadri
Department of Head and Neck Surgery, Roswell Park Cancer Institute, Buffalo, New York.
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Timothy F. Burns
University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
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Umamaheswar Duvvuri
University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.Department of Otolaryngology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.VA Pittsburgh Health System, Pittsburgh, Pennsylvania.
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  • For correspondence: duvvuriu@upmc.edu
DOI: 10.1158/1078-0432.CCR-17-1561
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Abstract

Purpose: TMEM16A is a calcium-activated chloride channel that is amplified in a variety of cancers, including 30% of head and neck squamous cell carcinomas (HNSCCs), raising the possibility of an anti-apoptotic role in malignant cells. This study investigated this using a multimodal, translational investigation.

Experimental Design: Combination of (i) in vitro HNSCC cell culture experiments assessing cell viability, apoptotic activation, and protein expression (ii) in vivo studies assessing similar outcomes, and (iii) molecular and staining analysis of human HNSCC samples.

Results: TMEM16A expression was found to correlate with greater tumor size, increased Erk 1/2 activity, less Bim expression, and less apoptotic activity overall in human HNSCC. These findings were corroborated in subsequent in vitro and in vivo studies and expanded to include a cisplatin-resistant phenotype with TMEM16A overexpression. A cohort of 41 patients with laryngeal cancer demonstrated that cases that recurred after chemoradiation failure were associated with a greater TMEM16A overexpression rate than HNSCC that did not recur.

Conclusions: Ultimately, this study implicates TMEM16A as a contributor to tumor progression by limiting apoptosis and as a potential biomarker of more aggressive disease. Clin Cancer Res; 1–9. ©2017 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Received June 6, 2017.
  • Revision received July 27, 2017.
  • Accepted September 7, 2017.
  • ©2017 American Association for Cancer Research.
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Published OnlineFirst November 7, 2017
doi: 10.1158/1078-0432.CCR-17-1561

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TMEM16A/ANO1 Inhibits Apoptosis Via Downregulation of Bim Expression
Neal R. Godse, Nayel Khan, Zachary A. Yochum, Roberto Gomez-Casal, Carolyn Kemp, Daniel J. Shiwarski, Raja S. Seethala, Scott Kulich, Mukund Seshadri, Timothy F. Burns and Umamaheswar Duvvuri
Clin Cancer Res November 7 2017 DOI: 10.1158/1078-0432.CCR-17-1561

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TMEM16A/ANO1 Inhibits Apoptosis Via Downregulation of Bim Expression
Neal R. Godse, Nayel Khan, Zachary A. Yochum, Roberto Gomez-Casal, Carolyn Kemp, Daniel J. Shiwarski, Raja S. Seethala, Scott Kulich, Mukund Seshadri, Timothy F. Burns and Umamaheswar Duvvuri
Clin Cancer Res November 7 2017 DOI: 10.1158/1078-0432.CCR-17-1561
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Clinical Cancer Research
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