Loss of BNIP3 expression is a late event in pancreatic cancer contributing to chemoresistance and worsened prognosis

Erkan, Mert; Kleeff, Jörg; Espósito, Irene; Giese, Thomas; Ketterer, Knut; Büchler, Markus W.; Giese, N.; Frieß, Helmut

doi:10.1038/sj.onc.1208642

Cited by 190 publications

(166 citation statements)

References 59 publications

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“…In our study, there was low efficiency of Runx2 silencing, although the current protocol used for siRNA transfection has been used for other genes (Berberat et al, 2005;Erkan et al, 2005;Kayed et al, 2005). Furthermore, two additional Runx2 siRNA sequences were used, and these exhibited even lower silencing efficiencies than the one that was used in the final experiments.…”

Section: Discussionmentioning

confidence: 89%

Regulation and functional role of the Runt-related transcription factor-2 in pancreatic cancer

et al. 2007

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Recent evidence suggests that Runt-related transcription factors play a role in different human tumours. In the present study, the localisation of the Runt-related transcription factor-2 (Runx2), its transcriptional activity, as well as its regulation of expression was analysed in human pancreatic ductal adenocarcinoma (PDAC). Quantitative real-time PCR and immunohistochemistry were used for Runx2 expression and localisation analysis. Runt-related transcription factor-2 expression was silenced using specific siRNA oligonucleotides in pancreatic cancer cells (Panc-1) and immortalised pancreatic stellate cells (IPSCs). Overexpression of Runx2 was achieved using a full-length expression vector. TGF-b1, BMP2, and other cytokines were assessed for their potential to regulate Runx2 expression. There was a 6.1-fold increase in median Runx2 mRNA levels in PDAC tissues compared to normal pancreatic tissues (Po0.0001). Runt-related transcription factor-2 was localised in pancreatic cancer cells, tubular complexes, and PanIN lesions of PDAC tissues as well as in tumour-associated fibroblasts/stellate cells. Coculture of IPSCs and Panc-1 cells, as well as treatment with TGF-b1 and BMP2, led to increased Runx2 expression in Panc-1 cells. Runt-related transcription factor-2 overexpression was associated with decreased MMP1 release as well as decreased growth and invasion of Panc-1 cells. These effects were reversed by Runx2 silencing. In conclusion, Runx2 is overexpressed in PDAC, where it is regulated by certain cytokines such as TGF-b1 and BMP2 in an auto-and paracrine manner. In addition, Runx2 has the potential to regulate the transcription of extracellular matrix modulators such as SPARC and MMP1, thereby influencing the tumour microenvironment.

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Section: Discussionmentioning

confidence: 89%

Regulation and functional role of the Runt-related transcription factor-2 in pancreatic cancer

et al. 2007

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“…The amount of nuclear versus cytoplasmic BNIP3 expression in different tumor types is shown in Table 2 and discussed below. Nuclear BNIP3 is detected in GBM tumors, 57 nonsmall cell lung tumors, 62 cervical tumors, 59 breast tumors 61 and prostate tumors, 56 and a perinuclear BNIP3 staining pattern is observed in pancreatic tumors 72 and colorectal adenocarcinomas. 69 In prostate tumors, there is a correlation between cytoplasmic BNIP3 expression and Gleason score, age AR and GLUT1 expression, but nuclear BNIP3 did not correlate with any clinicopathological factors.…”

Section: Bnip3mentioning

confidence: 99%

“…The more aggressive subclass A HCC showed a higher level of bnip3 promoter methylation than the less aggressive B type. 72 bnip3 gene was found to be methylated in multiple myeloma (MM) patient samples and was significantly correlated with poor patient survival rates. Trichostatin A (HDAC inhibitor) and Aza-dC treatment of MM cell lines lead to an increase in the expression of BNIP3.…”

Section: Bnip3mentioning

confidence: 99%

“…70,71 Shorter patient survival correlated with low BNIP3 expression. 72 Knocking down BNIP3 expression with siRNA resulted in resistance to fluorouracil (5-FU) and gemcitabine, the most common chemotherapeutic treatments for patients with PDAC. 72 S100A4 has been reported to inhibit BNIP3 expression in PDAC cell lines that have unmethylated BNIP3 promoters, also contributing to gemcitabine resistance.…”

Section: Bnip3mentioning

confidence: 99%

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The role of Bcl-2 family member BNIP3 in cell death and disease: NIPping at the heels of cell death

2009

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Bcl-2 nineteen-kilodalton interacting protein (BNIP3) is a BH-3-only Bcl-2 family member whose expression levels increase during stress such as hypoxia through hypoxia-inducing factor-1-dependent or -independent mechanisms. When BNIP3 expression is induced, it localizes to the mitochondria and triggers a loss of membrane potential, and an increase in the reactive oxygen species production, which often leads to cell death. Cells under normal growth conditions suppress BNIP3 expression through transcriptional repression. There is considerable debate in the literature regarding what type of cell death is induced by BNIP3. It has been observed that BNIP3 could induce necrosis, autophagy and/or apoptosis. In contrast, other studies indicate that BNIP3 could promote cell survival. Besides its cell death regulation, BNIP3 plays a key role in the pathogenicity of many diseases. In cardiac infarction, loss of BNIP3 expression has been shown to reduce the number of damaged cardiomyocytes after ischemia and reperfusion. BNIP3 expression also plays an important role in the deregulation of cell death in many cancers. In this review, we will discuss the different and often contradictory mechanisms of BNIP3 regulation of cell death and the role that BNIP3 may play in diseases. Bcl-2 nineteen-kilodalton interacting protein (BNIP3) belongs to the Bcl-2 homology domain (BH3)-only Bcl-2 family members because it only contains a putative BH3 domain. 1 The other major domains found in BNIP3 are the PEST domain that targets BNIP3 for degradation, a conserved domain that is conserved from Caenorhabditis elegans to humans and a transmembrane (TM) domain, which targets BNIP3 to the mitochondria (Figure 1). 2 BH3-only containing proteins act as rheostats regulating apoptosis through their BH3 domain by binding to antiapoptotic Bcl-2 family members. However, BNIP3 differs from these members, as its BH3 domain fails to interact with antiapoptotic Bcl-2 family members. 3 Furthermore, deletions of the BH3 domain fail to affect the ability of BNIP3 to induce cell death. 4 Unlike other BH3-only family members, BNIP3 interacts with Bcl-2 and Bcl-X L through its TM domain and N terminus (amino acids 1-49). 3 Deletion of the TM domain blocks the ability of BNIP3 to induce cell death. 4 BNIP3 migrates at 30 and 60 kDa, indicating that BNIP3 is a protein that forms homodimers. This homodimerization is primarily through the TM domain of BNIP3. The unique structure of the TM domain suggests that BNIP3 dimers could act as proton channels in the outer mitochondrial membrane increasing ion conductance. 5 Serine 172 and histidine (His) 173 are residues that are present in the dimerization interface of BNIP3. These residues interact by hydrogen bonds and are essential for dimer formation. 6 Furthermore, mutation of the His 173 to alanine completely abrogated the ability of BNIP3 to induce cell death. 7 Bcl-2 and Bcl-X L can compete for binding to the TM domain, which blocks BNIP3 homodimerization and abrogates the ability of BNIP3 to induce cell death (Fi...

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“…Erkan et al and Akada et al showed that silencing of BNIP3 by small interfering RNA (siRNA) correlated with increased chemoresistance. 29,30 Mahon et al showed that the knockdown of S100A4, a repressor of the BNIP3 promoter-mediated reporter gene expression, resulted in an elevated expression of BNIP3 and the activation of apoptotic mediators in PC cell lines, resulting in an increased sensitivity to gemcitabine treatment. 12 The treatment by Wack et al with adenoviral systems for proapoptotic Bax and TNF-related apoptosis-inducing ligand (TRAIL) expression targeting, using the human telomerase reverse transcriptase (hTERT) promoter, resulted in high-level expression of Bax and TRAIL, genes directly related to apoptosis induction in gemcitabine-resistant cell lines with a significant tumor regression and prolongation of in vivo survival.…”

Section: Apoptosismentioning

confidence: 99%

Epigenetic markers for chemosensitivity and chemoresistance in pancreatic cancer—A review

Dhayat

Mardin

Mees

et al. 2011

Intl Journal of Cancer

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Adjuvant first-line gemcitabine monochemotherapy presents a standard treatment for patients with advanced pancreatic adenocarcinoma and improves overall survival in chemosensitive patients. Nonetheless, 6-month progression-free survival remains below 15%, despite interdisciplinary approaches. The success of gemcitabine treatment is disappointing and-in the absence of reliable tumor markers-challenging to quantify. Epigenetic alterations have been recently identified to take on important roles in cancer development and possibly cancer treatment. In this context, microRNAs are becoming increasingly acknowledged as useful biomarkers for classifying cancers and providing information on their chemo-and radiosensitivity. This review illustrates the potential of genetic and epigenetic markers in the prediction of chemosensitivity in pancreatic cancer patients and in the monitoring of their response rates to adjuvant therapy.

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Loss of BNIP3 expression is a late event in pancreatic cancer contributing to chemoresistance and worsened prognosis

Cited by 190 publications

References 59 publications

Regulation and functional role of the Runt-related transcription factor-2 in pancreatic cancer

Regulation and functional role of the Runt-related transcription factor-2 in pancreatic cancer

The role of Bcl-2 family member BNIP3 in cell death and disease: NIPping at the heels of cell death

Epigenetic markers for chemosensitivity and chemoresistance in pancreatic cancer—A review

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