Background: New pharmacologic targets are urgently needed to treat or prevent lung cancer, the most common\r\ncause of cancer death for men and women. This study identified one such target. This is the canonical Wnt\r\nsignaling pathway, which is deregulated in cancers, including those lacking adenomatous polyposis coli or �Ÿ-catenin\r\nmutations. Two poly-ADP-ribose polymerase (PARP) enzymes regulate canonical Wnt activity: tankyrase (TNKS) 1\r\nand TNKS2. These enzymes poly-ADP-ribosylate (PARsylate) and destabilize axin, a key component of the �Ÿ-catenin\r\nphosphorylation complex.\r\nMethods: This study used comprehensive gene profiles to uncover deregulation of the Wnt pathway in murine\r\ntransgenic and human lung cancers, relative to normal lung. Antineoplastic consequences of genetic and\r\npharmacologic targeting of TNKS in murine and human lung cancer cell lines were explored, and validated in vivo\r\nin mice by implantation of murine transgenic lung cancer cells engineered with reduced TNKS expression relative\r\nto controls.\r\nResults: Microarray analyses comparing Wnt pathway members in malignant versus normal tissues of a murine\r\ntransgenic cyclin E lung cancer model revealed deregulation of Wnt pathway components, including TNKS1 and\r\nTNKS2. Real-time PCR assays independently confirmed these results in paired normal-malignant murine and human\r\nlung tissues. Individual treatments of a panel of human and murine lung cancer cell lines with the TNKS inhibitors\r\nXAV939 and IWR-1 dose-dependently repressed cell growth and increased cellular axin 1 and tankyrase levels. These\r\ninhibitors also repressed expression of a Wnt-responsive luciferase construct, implicating the Wnt pathway in\r\nconferring these antineoplastic effects. Individual or combined knockdown of TNKS1 and TNKS2 with siRNAs or\r\nshRNAs reduced lung cancer cell growth, stabilized axin, and repressed tumor formation in murine xenograft and\r\nsyngeneic lung cancer models.\r\nConclusions: Findings reported here uncovered deregulation of specific components of the Wnt pathway in both\r\nhuman and murine lung cancer models. Repressing TNKS activity through either genetic or pharmacological\r\napproaches antagonized canonical Wnt signaling, reduced murine and human lung cancer cell line growth, and\r\ndecreased tumor formation in mouse models. Taken together, these findings implicate the use of TNKS inhibitors to\r\ntarget the Wnt pathway to combat lung cancer.
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