Silencing of X-linked inhibitor of apoptosis (XIAP) decreases gemcitabine resistance of pancreatic cancer cells.
BACKGROUND
The X-linked inhibitor of apoptosis (XIAP) belongs to a family of proteins that suppresses apoptosis by inhibition of caspases in some cancers. It confers resistance to apoptosis induction by chemotherapeutic agents. The aim of this study was to evaluate the influence of XIAP in pancreatic cancer.


METHODS
Tissue samples from 43 patients with pancreatic adenocarcinoma (median age of 67 years, range from 39-81 years) were analyzed. Pancreatic samples from healthy organ donors (10) and chronic pancreatitis patients (10) served as controls. XIAP expression and localization analysis was carried out by quantitative RT-PCR and immunohistochemistry (IHC). XIAP silencing was achieved by transfection of specifically designed siRNA oligonucleotides. Proliferation and chemotherapy experiments were performed by MTT cell growth assays.


RESULTS
There was a 2.1-fold increase of median XIAP mRNA levels in pancreatic cancers compared to controls. Kaplan-Meier analysis indicated a tendency for reduced patient survival with increasing levels of XIAP mRNA (higher levels: 13.4 months; lower levels: 16.1 months). IHC revealed strong XIAP staining in tubular complexes and pancreatic cancer cells. XIAP silencing resulted in a slight reduction of the proliferation of Capan-1 and T3M4 pancreatic cancer cells. In addition, XIAP silencing resulted in increased sensitivity of both cell lines to gemcitabine.


CONCLUSIONS
XIAP is overexpressed in pancreatic cancer and contributes to chemoresistance. Interfering with this pathway may have potential therapeutic role in the treatment of this disease.
Shrikhande
Shailesh V
SV
Department of General Surgery, University of Heidelberg, Heidelberg, Germany.
Kleeff
Jörg
J
Kayed
Hany
H
Keleg
Shereen
S
Reiser
Carolin
C
Giese
Thomas
T
Büchler
Markus W
MW
Esposito
Irene
I
Friess
Helmut
H
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D017209:Apoptosis; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D020868:Gene Silencing; D006801:Humans; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D010179:Pancreas / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D050500:Pancreatitis, Chronic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051636:X-Linked Inhibitor of Apoptosis Protein; D003841:Deoxycytidine; D020169:Caspases; D000093542:Gemcitabine