Document Detail

Targeting X-linked inhibitor of apoptosis protein to increase the efficacy of endoplasmic reticulum stress-induced apoptosis for melanoma therapy.
MedLine Citation:
PMID:  20520630     Owner:  NLM     Status:  MEDLINE    
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.
Emma L Hiscutt; David S Hill; Shaun Martin; Ryan Kerr; Andrew Harbottle; Mark Birch-Machin; Christopher P F Redfern; Simone Fulda; Jane L Armstrong; Penny E Lovat
Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-06-03
Journal Detail:
Title:  The Journal of investigative dermatology     Volume:  130     ISSN:  1523-1747     ISO Abbreviation:  J. Invest. Dermatol.     Publication Date:  2010 Sep 
Date Detail:
Created Date:  2010-08-16     Completed Date:  2010-09-16     Revised Date:  2012-06-21    
Medline Journal Info:
Nlm Unique ID:  0426720     Medline TA:  J Invest Dermatol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2250-8     Citation Subset:  IM    
Dermatological Sciences, Institute of Cellular Medicine, Newcastle upon Tyne, UK.
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MeSH Terms
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects,  physiology
Boronic Acids / pharmacology*
Drug Resistance, Neoplasm
Endoplasmic Reticulum / physiology
Fenretinide / pharmacology*
Gene Expression Regulation, Neoplastic
Genes, ras / physiology
Melanoma / drug therapy*,  metabolism,  pathology
Middle Aged
Mutation / genetics
Nevus, Pigmented / drug therapy,  metabolism,  pathology
Proto-Oncogene Proteins B-raf / genetics
Pyrazines / pharmacology*
RNA, Small Interfering
Skin Neoplasms / drug therapy*,  metabolism,  pathology
Stress, Physiological / physiology
X-Linked Inhibitor of Apoptosis Protein / antagonists & inhibitors*,  genetics,  metabolism
Reg. No./Substance:
0/Antineoplastic Agents; 0/Boronic Acids; 0/Pyrazines; 0/RNA, Small Interfering; 0/X-Linked Inhibitor of Apoptosis Protein; 0/XIAP protein, human; 0/bortezomib; 65646-68-6/Fenretinide; EC protein, human; EC Proteins B-raf
Comment In:
J Invest Dermatol. 2010 Sep;130(9):2169-72   [PMID:  20711206 ]
J Invest Dermatol. 2011 Mar;131(3):797   [PMID:  21068753 ]

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