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

Abstract

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.

The HIF1α-inducible pro-cell death gene BNIP3 is a novel target of SIM2s repression through cross-talk on the hypoxia response element

“…BNIP3 has long been regarded as a pro-apoptotic Bcl-2 family member (reviewed in Lee and Paik (2006) and Burton and Gibson (2009)). Silencing of BNIP3 correlates to increased pancreatic and colon tumour cell survival in vitro, and tumour progression, chemoresistance and worsened prognosis in vivo (de Angelis et al, 2004;Okami et al, 2004;Akada et al, 2005;Erkan et al, 2005;Bacon et al, 2007;Ishiguro et al, 2007;Mahon et al, 2007). Notably, these are two of the tumour types in which SIM2s is found to be aberrantly up-regulated (DeYoung et al, 2002(DeYoung et al, , 2003a.…”

Silencing of BNIP3 Results from Promoter Methylation by DNA Methyltransferase 1 Induced by the Mitogen-Activated Protein Kinase Pathway

“…The promoter of BNIP3 is located within a CpG island and is methylated in most pancreatic cancer cell lines (Abe et al, 2005;Akada et al, 2005;Erkan et al, 2005). Restoration of BNIP3 expression by the methyltransferase inhibitor, 5-aza-2-deoxycytidine, leads to the death of pancreatic cancer cells in response to hypoxia.…”

Role of ASC in hypoxia-mediated cell death in pancreatic cancer

“…It has also been reported that HIF-1α induces both pro-apoptotic (BNIP3, NOXA, NIX, RTP801) and anti-apoptotic (FOXO3, IAP-2 and survivin) genes (19)(20)(21)(22)(23). For each cellular phenotype, the death or survival induced by hypoxia seems to depend on degree.…”