Targeting X-Linked Inhibitor of Apoptosis Protein to Increase the Efficacy of Endoplasmic Reticulum Stress-Induced Apoptosis for Melanoma Therapy
| Autor: | Simone Fulda, Jane L. Armstrong, Shaun Martin, Ryan Kerr, Andrew Harbottle, Emma L. Hiscutt, Mark A. Birch-Machin, Penny E. Lovat, D. S. Hill, Christopher P.F. Redfern |
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| Rok vydání: | 2010 |
| Předmět: |
Male
Proto-Oncogene Proteins B-raf Skin Neoplasms Fenretinide Antineoplastic Agents Apoptosis X-Linked Inhibitor of Apoptosis Protein Dermatology In Vitro Techniques Inhibitor of apoptosis Endoplasmic Reticulum Biochemistry Small hairpin RNA Bortezomib chemistry.chemical_compound Stress Physiological medicine Humans RNA Small Interfering Melanoma Molecular Biology Nevus Pigmented business.industry Cell Biology Middle Aged medicine.disease Boronic Acids XIAP Gene Expression Regulation Neoplastic Genes ras chemistry Drug Resistance Neoplasm Pyrazines Immunology Cutaneous melanoma Cancer cell Mutation Cancer research Female business medicine.drug |
| Zdroj: | Journal of Investigative Dermatology. 130(9):2250-2258 |
| ISSN: | 0022-202X |
| DOI: | 10.1038/jid.2010.146 |
| Popis: | Melanoma remains notoriously resistant to current chemotherapeutics, leaving an acute need for novel therapeutic approaches. The aim of this study was to determine the prognostic and therapeutic significance of X-linked inhibitor of apoptosis protein (XIAP) in melanoma through correlation of XIAP expression with disease stage, RAS/RAF mutational status, clinical outcome, and susceptibility to endoplasmic reticulum (ER) stress-induced cell death. XIAP expression and N-RAS/B-RAF mutational status were retrospectively determined in a cohort of 55 primary cutaneous melanocytic lesions selected and grouped according to the American Joint Committee on Cancer staging system. Short hairpin RNA interference of XIAP was used to analyze the effect of XIAP expression on ER stress-induced apoptosis in response to fenretinide or bortezomib in vitro. The results showed that XIAP positivity increased with progressive disease stage, although there was no significant correlation between XIAP positivity and combined N-RAS/B-RAF mutational status or clinical outcome. However, XIAP knockdown significantly increased ER stress-induced apoptosis of melanoma cells in a caspase-dependant manner. The correlation of XIAP expression with disease stage, as well as data showing that XIAP knockdown significantly increases fenretinide and bortezomib-induced apoptosis of metastatic melanoma cells, suggests that XIAP may prove to be an effective therapeutic target for melanoma therapy. |
| Databáze: | OpenAIRE |
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