IL-23R is epigenetically regulated and modulated by chemotherapy in non-small cell lung cancer

Baird, Anne-Marie, Dockry, Éilis, Daly, Anne, Stack, Emma, Doherty, Derek G., O'Byrne, Kenneth J., & Gray , Steven G. (2013) IL-23R is epigenetically regulated and modulated by chemotherapy in non-small cell lung cancer. Frontiers in Oncology, 3, 162-1---9.

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Abstract

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.

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ID Code: 67764
Item Type: Journal Article
Refereed: Yes
Keywords: Acetylation, Apilimod, Epigenetics, IL-23R, Methylation, Non-small cell lung cancer, gemcitabine, interleukin 12, interleukin 23, interleukin 23R, unclassified drug, article, cell proliferation, chromatin immunoprecipitation, controlled study, CpG island, histone acetylation, human, human cell, lung adenocarcinoma, lung non small cell cancer, protein expression, protein processing, reverse transcription polymerase chain reaction, RNA isolation, upregulation
DOI: 10.3389/fonc.2013.00162
ISSN: 2234-943X
Subjects: Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > ONCOLOGY AND CARCINOGENESIS (111200)
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright © 2013 Baird , Dockry , Daly ,
Stack, Doherty , O’Byrne and Gray .
Copyright Statement: 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 copy-
right notices concerning any third-party
graphics etc.
Deposited On: 26 Feb 2014 01:11
Last Modified: 30 Jul 2014 01:53

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