Moderate Activation of the Apoptosis Inhibitor bcl-xL Worsens the Prognosis in Pancreatic Cancer

Frieß, Helmut; Zhao, Lu; Andrén‐Sandberg, Åke; Berberat, Pascal O.; Zimmermann, Arthur; Adler, Guido; Schmid, Roland M.; Büchler, Markus W.

doi:10.1097/00000658-199812000-00009

Cited by 104 publications

(76 citation statements)

References 37 publications

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“…Here, we could show that there is no NF-nB -dependent up-regulation in Panc-1 cells; hence, c-Flip seems to have no role in TRAIL resistance in Panc-1 cells. Bcl-x L , another NF-nB antiapoptotic target gene, has been shown before to be involved in chemoresistance and TRAIL resistance in an NF-nB -dependent way (82)(83)(84)(85). Inhibition of constitutive NF-nB by overexpression of InB-SR inhibited expression of Bcl-x L (61,83,86,87), and down-regulation of Bcl-x L protein sensitized Panc-1 to TRAIL-mediated apoptosis (88).…”

Section: Discussionmentioning

confidence: 99%

Constitutively Activated Nuclear Factor-κB, but not Induced NF-κB, Leads to TRAIL Resistance by Up-Regulation of X-Linked Inhibitor of Apoptosis Protein in Human Cancer Cells

Braeuer

Büneker

Mohr

et al. 2006

Molecular Cancer Research

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The tumor necrosis factor -related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis in most, but not all, cancer cells. The molecular factors regulating the sensitivity to TRAIL are still incompletely understood. The transcription factor nuclear factor-KB (NF-KB) has been implicated, but its exact role is controversial. We studied different cell lines displaying varying responses to TRAIL and found that TRAIL can activate NF-KB in all our cancer cell lines regardless of their TRAIL sensitivity. Inhibition of NF-KB via adenoviral expression of the IKB-A super-repressor only sensitized the TRAIL-resistant pancreatic cancer cell line Panc-1. Panc-1 cells harbor constitutively activated NF-KB, pointing to a possible role of preactivated NF-KB in protection from TRAIL. Furthermore, we could reduce X-linked inhibitor of apoptosis protein (XIAP) levels in Panc-1 cells by inhibition of constitutively activated NF-KB and sensitize Panc-1 cells to TRAIL by RNA interference against XIAP. These results implicate elevated XIAP levels caused by high basal NF-KB activity in TRAIL resistance and suggest that therapeutic strategies involving TRAIL can be abetted by inhibition of NF-KB and/or XIAP only in tumor cells with constitutively

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Section: Discussionmentioning

confidence: 99%

Constitutively Activated Nuclear Factor-κB, but not Induced NF-κB, Leads to TRAIL Resistance by Up-Regulation of X-Linked Inhibitor of Apoptosis Protein in Human Cancer Cells

Braeuer

Büneker

Mohr

et al. 2006

Molecular Cancer Research

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“…Pancreatic cancer progression is associated with increased expression of growth factor receptors and their ligands (18 -21), alterations in the level of expression of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs), which may result in an imbalance between these (22)(23)(24), alterations in antiapoptotic pathways (25)(26)(27), the loss of additional tumor suppressor gene function (28 -30), and the acquisition of neoangiogenic properties (31,32).…”

Section: Introductionmentioning

confidence: 99%

Comprehensive Analysis of Matrix Metalloproteinase and Tissue Inhibitor Expression in Pancreatic Cancer

Jones

Humphreys

Campbell

et al. 2004

Clinical Cancer Research

181

152

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Purpose: To enable the design of improved inhibitors of matrix metalloproteinases (MMPs) for the treatment of pancreatic cancer, the expression profiles of a range of MMPs and tissue inhibitors of MMPs (TIMPs) were determined.Experimental Design: Nine MMPs (MMPs 1-3, 7-9, 11, 12, and 14) and three TIMPs (TIMPs 1-3) were examined in up to 75 pancreatic ductal adenocarcinomas and 10 normal pancreata by immunohistochemistry. Eighteen additional pancreatic ductal adenocarcinomas and an additional eight normal pancreata were also analyzed by real-time reverse transcription-PCR and additionally for MMP-15.Results: There was increased expression by immunohistochemistry for MMPs 7, 8, 9, and 11 and TIMP-3 in pancreatic cancer compared with normal pancreas (P < 0.0001, 0.04, 0.0009, 0.005, and 0.0001, respectively). Real-time reverse transcription-PCR showed a significant increase in mRNA levels for MMP-11 in tumor tissue compared with normal pancreatic tissue (P ‫؍‬ 0.0005) and also significantly reduced levels of MMP-15 (P ‫؍‬ 0.0026). Univariate analysis revealed that survival was reduced by lymph node involvement (P ‫؍‬ 0.0007) and increased expression of MMP-7 (P ‫؍‬ 0.005) and (for the first time) MMP-11 (P ‫؍‬ 0.02) but not reduced by tumor grade, tumor diameter, positive resection margins, adjuvant treatment, or expression of the remaining MMPs and TIMPs. On multivariate analysis, only MMP-7 predicted shortened survival (P < 0.05); however, increased MMP-11 expression was strongly associated with lymph node involvement (P ‫؍‬ 0.0073). Conclusions:We propose that the principle specificity for effective inhibitors of MMPs in pancreatic cancer should be for MMP-7 with secondary specificity against MMP-11. Moreover, these studies indicate that MMP-7 expression is a powerful independent prognostic indicator and potentially of considerable clinical value.

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“…[43][44][45][46]64 In pancreatic cancer, although Bcl-2 has not demonstrated prognostic significance, 65 overexpression of Bcl-X L is associated with shorter patient survival. 66,67 Both Bcl-2 and Bcl-X L are expressed in malignant melanoma and their levels increase with progression of the disease. 68,69 In contrast to our current understanding of Bcl-2 and Bcl-X L , considerably less is known about the role of other antiapoptotic Bcl-2 family members in human malignancies.…”

Section: Deregulated Expression Of Bcl-2 and Bcl-x L In Human Malignamentioning

confidence: 99%

Recent advances in the development of anticancer agents targeting cell death inhibitors in the Bcl-2 protein family

Shangary

Johnson

2003

Leukemia

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Moderate Activation of the Apoptosis Inhibitor bcl-xL Worsens the Prognosis in Pancreatic Cancer

Cited by 104 publications

References 37 publications

Constitutively Activated Nuclear Factor-κB, but not Induced NF-κB, Leads to TRAIL Resistance by Up-Regulation of X-Linked Inhibitor of Apoptosis Protein in Human Cancer Cells

Constitutively Activated Nuclear Factor-κB, but not Induced NF-κB, Leads to TRAIL Resistance by Up-Regulation of X-Linked Inhibitor of Apoptosis Protein in Human Cancer Cells

Comprehensive Analysis of Matrix Metalloproteinase and Tissue Inhibitor Expression in Pancreatic Cancer

Recent advances in the development of anticancer agents targeting cell death inhibitors in the Bcl-2 protein family

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