مورد إلكتروني
Prognostic and therapeutic relevance of FLIP and procaspase-8 overexpression in non-small cell lung cancer
| العنوان: | Prognostic and therapeutic relevance of FLIP and procaspase-8 overexpression in non-small cell lung cancer |
|---|---|
| بيانات النشر: | Nature Research 2013-12-05 |
| تفاصيل مُضافة: | Riley, J S Hutchinson, R McArt, D G Crawford, N Holohan, C Paul, I Van Schaeybroeck, S Salto-Tellez, M Johnston, P G Fennell, D A Gately, K O'Byrne, K Cummins, R Kay, E Hamilton, P Stasik, Izabela Longley, D B |
| نوع الوثيقة: | Electronic Resource |
| مستخلص: | Non-small cell lung carcinoma remains by far the leading cause of cancer-related deaths worldwide. Overexpression of FLIP, which blocks the extrinsic apoptotic pathway by inhibiting caspase-8 activation, has been identified in various cancers. We investigated FLIP and procaspase-8 expression in NSCLC and the effect of HDAC inhibitors on FLIP expression, activation of caspase-8 and drug resistance in NSCLC and normal lung cell line models. Immunohistochemical analysis of cytoplasmic and nuclear FLIP and procaspase-8 protein expression was carried out using a novel digital pathology approach. Both FLIP and procaspase-8 were found to be significantly overexpressed in tumours, and importantly, high cytoplasmic expression of FLIP significantly correlated with shorter overall survival. Treatment with HDAC inhibitors targeting HDAC1-3 downregulated FLIP expression predominantly via post-transcriptional mechanisms, and this resulted in death receptor- and caspase-8-dependent apoptosis in NSCLC cells, but not normal lung cells. In addition, HDAC inhibitors synergized with TRAIL and cisplatin in NSCLC cells in a FLIP- and caspase-8-dependent manner. Thus, FLIP and procaspase-8 are overexpressed in NSCLC, and high cytoplasmic FLIP expression is indicative of poor prognosis. Targeting high FLIP expression using HDAC1–3 selective inhibitors such as entinostat to exploit high procaspase-8 expression in NSCLC has promising therapeutic potential, particularly when used in combination with TRAIL receptor-targeted agents. |
| مصطلحات الفهرس: | A100 - Pre-clinical medicine, B131 - Cellular pathology, B132 - Pathobiology, C131 - Applied cell biology, Article, PeerReviewed |
| URL: | 10.1038/cddis.2013.481 |
| الإتاحة: | Open access content. Open access content cc_by_4 |
| ملاحظة: | application/pdf English |
| أرقام أخرى: | UKLAN oai:clok.uclan.ac.uk:18163 Riley, J S, Hutchinson, R, McArt, D G, Crawford, N, Holohan, C, Paul, I, Van Schaeybroeck, S, Salto-Tellez, M, Johnston, P G et al (2013) Prognostic and therapeutic relevance of FLIP and procaspase-8 overexpression in non-small cell lung cancer. Cell Death and Disease, 4 (12). e951. 10.1038/cddis.2013.481 1365546934 |
| المصدر المساهم: | UNIV OF CENT LANCASHIRE From OAIster®, provided by the OCLC Cooperative. |
| رقم الأكسشن: | edsoai.on1365546934 |
| قاعدة البيانات: | OAIster |
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