Original Research ARTICLE
IL-23R is epigenetically regulated and modulated by chemotherapy in Non-Small Cell Lung Cancer
- 1Department of Clinical Medicine, Trinity College Dublin, Dublin, Ireland
- 2Thoracic Oncology Research Group, Institute of Molecular Medicine, St. James’s Hospital, Dublin, Ireland
- 3Department of Immunology, Trinity College Dublin, Dublin, Ireland
- 4HOPE Directorate, St. James’s Hospital, Dublin, Ireland
- 5Cancer Services, Princess Alexandra Hospital, Cancer and Ageing Research Program, Queensland University of Technology, Brisbane, Australia
The Interleukin-23 (IL-23)/IL-23R signaling axis is an important inflammatory pathway, involved in the stimulation and regulation of the T helper (Th) 17 lymphocytes, resulting in the production of IL-17. Aside from auto-immunity, this cytokine has also been linked to carcinogenesis and polymorphisms in the IL-23R gene are associated with an increased risk for the development of a number of different cancers. Activation of the IL-23 pathway results in the up-regulation of STAT3 and it is thought that the pathological consequences associated with this are in part due to the production of IL-17. We have previously identified IL-23A as pro-proliferative and epigenetically regulated in non-small cell lung cancer (NSCLC). The current study aims to evaluate IL-23R in greater detail in NSCLC. We demonstrate that IL-23R is expressed and epigenetically regulated in NSCLC through histone post-translation modifications and CpG island methylation. In addition, Gemcitabine treatment, a chemotherapy drug used in the treatment of NSCLC, resulted in the up-regulation of the IL-23R. Furthermore, Apilimod (STA 5326), a small molecule which blocks the expression of IL-23 and IL-12, reduced the proliferative capacity of NSCLC cells, particularly in the adenocarcinoma (A549) sub-type. Apilimod is currently undergoing investigation in a number of clinical trials for the treatment of auto-immune conditions such as Crohn’s disease and Rheumatoid Arthritis. Our results may have implications for treating NSCLC patients with Gemcitabine or epigenetic targeted therapies. However, Apilimod may possibly provide a new treatment avenue for NSCLC patients. Work is currently ongoing to further delineate the IL-23/IL-23R axis in this disease.
Keywords: IL-23R, non-small cell lung cancer, epigenetics, acetylation, methylation, apilimod
Citation: Baird A-M, Dockry É, Daly A, Stack E, Doherty DG, O’Byrne KJ and Gray SG (2013) IL-23R is epigenetically regulated and modulated by chemotherapy in Non-Small Cell Lung Cancer. Front. Oncol. 3:162. doi: 10.3389/fonc.2013.00162
Received: 27 March 2013; Accepted: 06 June 2013;
Published online: 19 June 2013.
Edited by:Markus Joerger, Kantonsspital St.Gallen, Switzerland
Reviewed by:Sacha I. Rothschild, University Hospital Basel, Switzerland
Markus Joerger, Kantonsspital St.Gallen, Switzerland
Copyright: © 2013 Baird, Dockry, Daly, Stack, Doherty, O’Byrne and Gray. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.
*Correspondence: Steven G. Gray, Thoracic Oncology Research Group, Trinity Centre for Health Sciences, Institute of Molecular Medicine, St James’s Hospital, Room 1.06, Dublin 8, Ireland e-mail: firstname.lastname@example.org