Abstract
BackgroundNew 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.MethodsThis 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.ResultsMicroarray 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.ConclusionsFindings 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.
Highlights
New pharmacologic targets are urgently needed to treat or prevent lung cancer, the most common cause of cancer death for men and women
Comprehensive microarray analyses compared non-transgenic murine lung, transgenic murine normal lung, and transgenic murine lung cancer. These analyses established Euclidean hierarchical clustering of each tissue by Wnt family member expression, with similar expression levels of these species detected in murine non-transgenic lung and transgenic normal lung tissue, but a different expression pattern in transgenic lung cancers
The authors saw very little in vivo antineoplastic effects from TNKS1 knockdown alone, in contrast to the significant growth effects we observed following TNKS1 and TNKS2 combined knockdown. We propose that this discrepancy is likely due to the ability of TNKS2 to compensate for TNKS1 in long-term knockdown, as is seen in in vivo xenograft studies lasting upwards of 60 days
Summary
New pharmacologic targets are urgently needed to treat or prevent lung cancer, the most common cause of cancer death for men and women. 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. Ligand binding engages a pathway involving Dishevelled (Dvl) that inhibits GSK3, allowing β-catenin to accumulate in a hypophosphorylated form This stabilized form of β-catenin can translocate to the nucleus, where it activates target gene transcription by complexing with T cell factor (TCF) and lymphoid enhancer-binding factor (LEF). In addition to key mediators of embryonic development, these target genes include critical growth-regulators such as myc and cyclin D1 [11,12]
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