Targeting X-linked inhibitor of apoptosis protein to increase the efficacy of endoplasmic reticulum stress-induced apoptosis for melanoma therapy.
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.
Dermatological Sciences, Institute of Cellular Medicine, Newcastle upon Tyne, UK.
Emma L
EL
Hiscutt
David S
DS
Hill
Shaun
S
Martin
Ryan
R
Kerr
Andrew
A
Harbottle
Mark
M
Birch-Machin
Christopher P F
CP
Redfern
Simone
S
Fulda
Jane L
JL
Armstrong
Penny E
PE
Lovat
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D019008:Drug Resistance, Neoplasm; D004721:Endoplasmic Reticulum / Q000502:physiology; D005260:Female; D017313:Fenretinide / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009508:Nevus, Pigmented / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D011719:Pyrazines / Q000494:pharmacology*; D034741:RNA, Small Interfering; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013312:Stress, Physiological / Q000502:physiology; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D034741:RNA, Small Interfering; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D017313:Fenretinide; D000069286:Bortezomib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf