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Open Access Highly Accessed Research article

Evidence for tankyrases as antineoplastic targets in lung cancer

Alexander M Busch1, Kevin C Johnson1, Radu V Stan2347, Aarti Sanglikar5, Yashi Ahmed67, Ethan Dmitrovsky178 and Sarah J Freemantle1*

Author Affiliations

1 From the Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, NH, 03755, USA

2 Heart and Vascular Research Center, Geisel School of Medicine at Dartmouth, Hanover, NH, 03755, USA

3 Department of Pathology, Geisel School of Medicine at Dartmouth, Hanover, NH, 03755, USA

4 Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH, 03755, USA

5 Center for Comparative Medicine and Research, Geisel School of Medicine at Dartmouth, Hanover, NH, 03755, USA

6 Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH, 03755, USA

7 Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Hanover, NH, 03755, USA

8 Department of Medicine, Geisel School of Medicine at Dartmouth, Hanover, NH, 03755, USA

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BMC Cancer 2013, 13:211  doi:10.1186/1471-2407-13-211

Published: 28 April 2013

Abstract

Background

New pharmacologic targets are urgently needed to treat or prevent lung cancer, the most common cause of cancer death for men and women. This study identified one such target. This is the canonical Wnt signaling pathway, which is deregulated in cancers, including those lacking adenomatous polyposis coli or β-catenin mutations. Two poly-ADP-ribose polymerase (PARP) enzymes regulate canonical Wnt activity: tankyrase (TNKS) 1 and TNKS2. These enzymes poly-ADP-ribosylate (PARsylate) and destabilize axin, a key component of the β-catenin phosphorylation complex.

Methods

This study used comprehensive gene profiles to uncover deregulation of the Wnt pathway in murine transgenic and human lung cancers, relative to normal lung. Antineoplastic consequences of genetic and pharmacologic targeting of TNKS in murine and human lung cancer cell lines were explored, and validated in vivo in mice by implantation of murine transgenic lung cancer cells engineered with reduced TNKS expression relative to controls.

Results

Microarray analyses comparing Wnt pathway members in malignant versus normal tissues of a murine transgenic cyclin E lung cancer model revealed deregulation of Wnt pathway components, including TNKS1 and TNKS2. Real-time PCR assays independently confirmed these results in paired normal-malignant murine and human lung tissues. Individual treatments of a panel of human and murine lung cancer cell lines with the TNKS inhibitors XAV939 and IWR-1 dose-dependently repressed cell growth and increased cellular axin 1 and tankyrase levels. These inhibitors also repressed expression of a Wnt-responsive luciferase construct, implicating the Wnt pathway in conferring these antineoplastic effects. Individual or combined knockdown of TNKS1 and TNKS2 with siRNAs or shRNAs reduced lung cancer cell growth, stabilized axin, and repressed tumor formation in murine xenograft and syngeneic lung cancer models.

Conclusions

Findings reported here uncovered deregulation of specific components of the Wnt pathway in both human and murine lung cancer models. Repressing TNKS activity through either genetic or pharmacological approaches antagonized canonical Wnt signaling, reduced murine and human lung cancer cell line growth, and decreased tumor formation in mouse models. Taken together, these findings implicate the use of TNKS inhibitors to target the Wnt pathway to combat lung cancer.

Keywords:
Lung cancer; Wnt pathway; Tankyrase inhibitors; TNKS; TNKS2