Silencing of X-linked inhibitor of apoptosis (XIAP) decreases gemcitabine resistance of pancreatic cancer cells.

Full Abstract

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. PATIENTS AND 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. CONCLUSION: 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.

Author information

Author/s: Shrikhande, Shailesh V (SV); 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);

Affiliation: Department of General Surgery, University of Heidelberg, Heidelberg, Germany.

Journal and publication information

Publication Type: Comparative Study; Journal Article; Research Support, Non-U.S. Gov't

Journal: Anticancer research (Anticancer Res), published in Greece. (Language: eng)

Reference: -2006 Sep-Oct; vol 26 (issue 5A) : pp 3265-73

Dates: Created 2006/11/10; Completed 2006/11/30;

PMID: 17094439, status: MEDLINE (last retrieved date: 2/18/2009)

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MeSH headings (categories)

This article was linked to the MeSH Headings (categories) shown below.

Adolescent
Adult
Aged
Aged, 80 and over
Antimetabolites, Antineoplastic - therapeutic use
Apoptosis
Carcinoma, Pancreatic Ductal - drug therapy; genetics; metabolism
Case-Control Studies
Caspases - metabolism
Cell Line, Tumor
Cell Proliferation
Deoxycytidine - analogs & derivatives; therapeutic use
Drug Resistance, Neoplasm - genetics
Female

Gene Silencing
Humans
Immunoblotting
Immunoenzyme Techniques
Male
Middle Aged
Pancreas - metabolism
Pancreatic Neoplasms - drug therapy; genetics; metabolism
Pancreatitis, Chronic - drug therapy; genetics; metabolism
RNA, Messenger - genetics; metabolism
RNA, Small Interfering - pharmacology
Reverse Transcriptase Polymerase Chain Reaction
Survival Rate
X-Linked Inhibitor of Apoptosis Protein - antagonists & inhibitors; genetics; metabolism

Note: Bold headings indicate primary MeSH headings or qualifiers.

Associated Chemicals: Antimetabolites, Antineoplastic (0) ; RNA, Messenger (0) ; RNA, Small Interfering (0) ; X-Linked Inhibitor of Apoptosis Protein (0) ; gemcitabine (103882-84-4) ; Deoxycytidine (951-77-9) ; Caspases (EC 3.4.22.-)

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