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

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.