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Intrinsic Chemoresistance to Gemcitabine Is Associated with Decreased Expression of BNIP3 in Pancreatic Cancer

Authors' Affiliations: ¹ Cancer Research UK Clinical Centre at Barts and London School of Medicine, London, United Kingdom and ² Division of Gastroenterological Surgery, Department of Surgery, Tohoku University School of Medicine, Sendai, Japan

Requests for reprints: Nicholas R. Lemoine, Molecular Oncology Unit, Cancer Research UK Clinical Centre at Barts and London School of Medicine, John Vane Science Building, Charterhouse Square, London EC1M 6BQ, United Kingdom. Phone: 44-20-7014-0420; Fax: 44-20-7014-0431; E-mail: nick.lemoine{at}cancer.org.uk.

Purpose: Although chemotherapy with gemcitabine is a common mode of treatment of pancreatic cancer, 75% of patients do not benefit from this therapy. It is likely that the sensitivity of cancer cells to gemcitabine is determined by a number of different factors.

Experimental Design: To identify genes that might contribute to resistance to gemcitabine, 15 pancreatic cancer cell lines were subjected to gemcitabine treatment. Simultaneously, gene expression profiling using a cDNA microarray to identify genes responsible for gemcitabine sensitivity was performed.

Results: The pancreatic cancer cell lines could be classified into three groups: a gemcitabine "sensitive," an "intermediate sensitive," and a "resistant" group. Microarray analysis identified 71 genes that show differential expression between gemcitabine-sensitive and -resistant cell lines including 27 genes relatively overexpressed in sensitive cell lines whereas 44 genes are relatively overexpressed in resistant cell lines. Among these genes, 7 genes are potentially involved in the phosphatidylinositol 3-kinase/Akt pathway. In addition to this major signaling pathway, Bcl2/adenovirus E1B 19 kDa protein interacting protein (BNIP3), a Bcl-2 family proapoptotic protein, was identified as being expressed at lower levels in drug-resistant pancreatic cancer cell lines. In an analysis of 21 pancreatic cancer tissue specimens, more than 90% showed down-regulated expression of BNIP3. When expression of BNIP3 was suppressed using small interfering RNA, gemcitabine-induced cytotoxicity in vitro was much reduced.

Conclusions: These results suggest that BNIP3 and the phosphatidylinositol 3-kinase/Akt pathway may play an important role in the poor response to gemcitabine treatment in pancreatic cancer patients.

Key Words: cDNA microarray • drug resistance • Akt • PI3K • siRNA

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