Abstract 2311: IL-1β induction of EMT and impact on drug sensitivity in NSCLC

Abstract

Abstract Pulmonary diseases associated with a heightened risk of lung cancer, such as emphysema, chronic obstructive pulmonary disease and pulmonary fibrosis, show both increased and deregulated inflammation. Tobacco smoke exposure is associated with chronic airway inflammation and is the strongest risk factor for the development of lung cancer. Inflammatory mediators and inflammatory cells are overexpressed in the pulmonary microenvironment of both smokers and patients with non-small cell lung cancer (NSCLC). Here we report that exposure to IL-1β, a pro-inflammatory cytokine, induces epithelial-mesenchymal tranisition (EMT) in a subset of NSCLC cell lines. An important feature of mesenchymal cells is their ability to migrate independently and invade locally - which is considered a prerequisite for metastasis. Following IL-1β exposure there are changes in cellular morphology, disruption of the cells' ability to form spheroids in 3-D culture and increased motility. There is also an upregulation of Slug (SNAI1), N-cadherin and Vimentin and downregulation of E-cadherin. Slug, a transcriptional repressor of E-cadherin, is found via chromatin immunoprecipitation to be bound to the E-cadherin promoter following IL-1β exposure. Blocking Slug expression using siRNA inhibits this downregulation of E-cadherin. IL-1β has many well-characterized effects on signaling pathways and protein expression, including the upregulation of COX-2 which has been shown previously to decrease E-cadherin expression. However, the IL-1β-mediated downregulation of E-cadherin presented here is COX-2 independent. Blocking COX-2 activity with celecoxib or by use of cells expressing COX-2 antisense does not abrogate the IL-1β dependent E-cadherin downregulation. These effects are important due their possible impact on cancer therapy. E-cadherin expression is implicated as a marker of sensitivity to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), which are used as therapy for NSCLC. The loss of E-cadherin is associated with lack of response to EGFR TKIs. Factors which contribute to EMT therefore are important not only in terms of their impact on malignancy and tumor progression but also because they can influence drug sensitivity. Our work shows apoptosis, measured by an increase in cleaved PARP, is induced in A549 cells following 24 hours of erlotinib (10µM) treatment. However, pretreating these cells with IL-1β blocks erlotinib-induced apoptosis. This suggests that the chronic presence of IL-1β in the tumor microenvironment may negatively impact the efficacy of some drug therapies. In addition, in H1437 cells, treatment with IL-1β led to a large increase in the expression of survivin, an anti-apoptotic protein. In light of IL-1β's multiple effects, its presence in the pulmonary microenvironment may play a specific role in setting the stage for metastasis and promoting resistance to targeted prevention and therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2311.