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Biomedical subjects

Guido Adler

Publications and source records attributed to Guido Adler.

At least 55 records · Page 3Linked to original sources
PubMed2003

Mitogenic and antiapoptotic role of constitutive NF-kappaB/Rel activity in pancreatic cancer.

The transcription factor NF-kappaB/Rel was found to be constitutively activated in human pancreatic cancer. RelA is present in the nucleus in primary human pancreatic cancer samples as well as in pancreatic cancer cell lines. NF-kappaB/Rel-binding activity consists of NF-kappaB1(p50) and RelA(p65). Constitutive NF-kappaB/Rel activity correlates with IkappaB kinase (IKK) activity and can be blocked by dominant negative mutants of IKKbeta and to a lesser extent by IKKalpha. Constitutive NF-kappaB/Rel activity and the transactivation potential of RelA(p65) can be inhibited by dominant negative mutant Ras, the PI3 kinase inhibitor LY294002, or dominant negative mutant Akt kinase. Transfection of a dominant negative mutant epidermal growth factor receptor (EGF-R), EGF-R kinase inhibitor Tyrphostin and LY 294002 blocked IKK activity and NF-kappaB-dependent transcription. Inhibition of constitutive IKK or NF-kappaB/Rel activity increased the number of apoptotic cells. Stably expressing a nondegradable form of IkappaBalpha inhibited anchorage-dependent and -independent proliferation in MiaPaCa2 and Panc1 cells. Our data demonstrate that an EGF-R/Ras/PI3 kinase/Akt/IKK-dependent pathway contributes to constitutive NF-kappaB/Rel activity in pancreatic cancer. Inhibition of NF-kappaB/Rel activity reveals a mitogenic and antiapoptotic role for NF-kappaB/Rel in pancreatic cancer.

Adenocarcinoma↗
PubMed2003

Pattern of secondary genomic changes in pancreatic tumors of Tgf alpha/Trp53+/- transgenic mice.

Trp53(+/-) mice overexpressing Tgfalpha in a pancreas-specific manner represent a well-established animal model for pancreatic cancer. In this study we analyzed 38 pancreatic adenocarcinomas of these mice for secondary genomic changes by comparative genomic hybridization (CGH), loss of heterozygosity (LOH) analysis, real-time PCR, and methylation-specific analysis. CGH screening of the tumors revealed a recurrent pattern of genomic changes. In more than 50% of the tumors, chromosome 11 was affected. The gain of the proximal part spans about 16 cM, including the genes for Egfr, Rel, and Stk10. The distal part of chromosome 11, which contains the Trp53 locus, was deleted. LOH analysis proved that almost all tumors segregate the wild-type Trp53 allele. The Cdkn2a locus on chromosome 4 was inactivated by hypermethylation in 55% of all tumors. In addition, two other changes were detected in a mutually exclusive manner: overrepresentation of part of chromosome 15, or more rarely, loss of the distal part of chromosome 14. Together these data suggest the induction of a uniform pattern of secondary genomic changes in this transgenic tumor model for pancreatic cancer.

Adenocarcinoma↗
PubMed2003

Quantitative ultrasound of the proximal phalanges and dual-energy X-ray absorptiometry in Crohn's disease patients with osteopenia.

BACKGROUND: Osteopenia and osteoporosis are frequent complications in Crohn's disease, and these features are associated with an increased risk of vertebral and appendicular fractures. Bone mineral density (BMD) measurements are widely accepted to assess the fracture risk in postmenopausal osteoporosis. In recent years, quantitative ultrasound (QUS) has become attractive for the diagnosis of osteopenia as a nonionizing method. The aim of the present study was to investigate QUS and BMD measurements in osteopenic patients with Crohn's disease. METHODS: BMD of the lumbar spine and femoral neck and QUS of proximal phalanges II-V (DBM Sonic 1200; IGEA) were performed prospectively in 171 patients with Crohn's disease. The amplitude-dependent sound-of-speed (AD-SoS) and the ultrasound bone profile score (UBPS) were calculated using the WinSonic PRO 1.1 software program. X-ray examination of the spine was performed in 131 patients. Vertebral deformity was morphometrically defined according to the published methods of McCloskey and Eastell. RESULTS: BMD of the lumbar spine and femoral neck correlated significantly (r = 0.62), but no correlation between BMD and QUS could be demonstrated. Vertebral deformities (VD) were detected in 28/131 (21.4%) patients. Two patients had a history of femoral fracture (FF). Lumbar BMD was lower in patients with either VD or FF than in those patients with no preexisting fractures (T-score: -2.46 vs -2.04; P = 0.0233). QUS parameters correlated negatively to patients' age but could not be used to discriminate between patients with and without VD/FF. CONCLUSIONS: Osteoporosis-related fractures are associated with a low lumbar bone density in Crohn's disease patients. QUS of the proximal phalanges cannot detect manifest osteoporosis in Crohn's disease patients and is therefore not valuable as a screening tool for these patients.

Absorptiometry, Photon↗
PubMed2003

Transgenic overexpression of the oncofetal RNA binding protein KOC leads to remodeling of the exocrine pancreas.

BACKGROUND & AIMS: To elucidate the function of the oncofetal RNA-binding protein, K-homologous (KH) domain containing protein overexpressed in cancer (KOC), we studied the effect of a constitutive reexpression of KOC in transgenic mice. METHODS: Transgenic mouse lines expressing KOC under the control of the mouse metallothionein promoter were generated and were shown to express the 69-kilodalton protein. Two mouse lines with moderate to strong gene expression of the transgene were further analyzed. RESULTS: The pancreas of KOC-transgenic mice showed progressive morphologic alterations, including an increased proliferation of acinar cells, acinar-ductal metaplasia, net loss of acinar tissue, and the appearance of numerous interstitial cells. Acinar-ductal metaplasia led to the development of duct-like structures exhibiting the characteristics of normal intralobular ducts. Interstitial cells expressed markers of endocrine or ductal differentiation. Nerve growth factor alpha (NGF-alpha) and the GTPase kir/Gem were identified as potential targets of KOC by expression profiling analyses. CONCLUSIONS: Reexpression of KOC in the transgenic model is apparently incompatible with the maintenance of a fully differentiated, adult acinar phenotype and may lead to a more fetal ductal phenotype via acinar-ductal metaplasia. This and the appearance of interstitial cells with a ductal and endocrine differentiation capacity suggest that transgenic reexpression of the oncofetal gene KOC may recapitulate a developmental program active during embryogenesis.

Animals↗
PubMed2003

Glial-derived neurotrophic factor regulates apoptosis in colonic epithelial cells.

BACKGROUND & AIMS: Ablation of the enteric glia leads to a fulminant hemorrhagic jejunoileitis. We hypothesized that glial-derived neurotrophic factor (GDNF) may be involved in mucosal protection of the gut. Therefore, we examined the regulation of GDNF and its receptor (GFR-alpha1) in colonic inflammation and its effects on colonic epithelial cell apoptosis. METHODS: The expression of GDNF and GFR-alpha1 was investigated in experimental colitis of rats and in human inflammatory bowel disease (IBD). GDNF-induced activation of Akt (protein kinase B [PKB]) and mitogen-activated protein kinase (MAPK) in the colonic epithelial cell lines HT-29 and SW480 was studied. Furthermore, the antiapoptotic potency of GDNF in SW480 cells was evaluated. RESULTS: GDNF was specifically up-regulated in experimental rat colitis and in IBD. In contrast, GFR-alpha1 was constitutively expressed in rat and human colonic epithelium. GDNF potently activated MAPK and Akt (PKB) in colonic epithelial cells. Moreover, GDNF strongly prevented apoptosis in SW480 cells. Our data show that GDNF-mediated protection against apoptosis depends on activation of the MAPK and phosphatidylinositol 3-kinase/Akt (PKB) pathways. CONCLUSIONS: GDNF is up-regulated in IBD and has strong antiapoptotic properties in colonic epithelial cells. This points to a novel role of the neurotrophic factor GDNF for mucosal protection and regeneration in IBD.

Apoptosis↗
PubMed2003

Recurrent abdominal pain in children: evidence from a population-based study that social and familial factors play a major role but not Helicobacter pylori infection.

OBJECTIVE: To analyze the relationship between social and familial factors, Helicobacter pylori infection and recurrent abdominal pain (RAP) in children in a population-based cross-sectional study among 1221 preschool children aged 5-8 years. METHODS: H. pylori infection status was determined by 13C-urea breath test (13C-UBT) and information on medical history of the child and on RAP as well as on family demographics was obtained by a standardized questionnaire. RESULTS: Overall, 129 children (11.3%) were infected with H. pylori and 29 children were identified as having RAP within the past 3 months (2.5%). Analysis by multiple logistic regression demonstrated a clear relationship of RAP with living in a single parent household [odds ratio (OR) 2.9, 95% confidence interval (95% CI) 1.2-6.7], with parental history of peptic ulcer (OR 3.7, 95% CI 1.3-10.4) and with parental history of nonulcer gastrointestinal disorders (OR 5.3, 95% CI 2.1-13.2). By contrast, there was a nonsignificant relation between H. pylori infection and occurrence of RAP (OR 1.6, 95% CI 0.5-5.5). CONCLUSION: Social and familial factors play a major role but not H. pylori infection in RAP.

Abdominal Pain↗
PubMed2003

Helicobacter pylori infection and the occurrence and severity of gastrointestinal symptoms during pregnancy.

OBJECTIVE: We investigated the possible role of Helicobacter pylori infection in the occurrence and severity of gastrointestinal symptoms during pregnancy in a large group of mothers after delivery. STUDY DESIGN: Between November 2000 and November 2001, mothers were recruited after delivery at the Department of Gynecology and Obstetrics at the University of Ulm. Present H pylori infection was determined by (13)C-urea breath test. Associations between gastrointestinal symptoms during pregnancy (sickness, vomiting, increased saliva production, heartburn) and H pylori infection were quantified by crude and adjusted odds ratios with 95% CI. RESULTS: Twenty-three percent of the 898 mothers had a current H pylori infection. Eighty-four percent of the mothers reported at least one of the evaluated gastrointestinal symptoms, and 30% of the mothers reported at least one physician visit because of the severity of these symptoms. None of the analyzed gastrointestinal symptoms showed an association to a current H pylori infection after an adjustment for the covariates, even after a virulence marker of H pylori infection was taken into account. CONCLUSION: This study does not support an involvement of H pylori infection in the generation of gastrointestinal symptoms during pregnancy.

Adolescent↗
PubMed2003

Acute pancreatitis.

Acute pancreatitis is associated with significant morbidity and a mortality rate of approximately 8%. In severe pancreatitis, necrosis at the site of inflammation and remote organ failure develop in the course of disease. Pancreatic injury is initiated by molecular events in acinar cells. Premature activation of digestive enzymes, disturbances of intracellular calcium, and activation of transcription factors such as NF-kappaB characterize the initial phase of acute pancreatitis. The release of proinflammatory mediators and the recruitment of immune cells expand the local disturbances to a systemic inflammatory response associated with failure of distant organs such as lungs or kidney. The use of transgenic or knockout mice together with classic models of secretagogue-induced pancreatitis has provided considerable insight into the role of individual cellular or humoral factors in different stages of experimental pancreatitis. Transfer of these findings into clinical management or novel therapeutic strategies so far has had only very limited success. This may be due to the limitation of pancreatitis models to mimic completely the human disease. Therefore, a distinction between experimental models and clinical acute pancreatitis has to be maintained. The first part of this review will therefore concentrate on the initiation of acinar cell injury in experimental pancreatitis. Novel insights covering the mechanism by which local pancreatic involvement expands into systemic inflammation described in the second part. Progress in the clinical management and treatment of acute pancreatitis in humans is the focus of the third part of this review.

Journal Article↗
PubMed2003

Effect of systemic glucocorticoid therapy on bone metabolism and the osteoprotegerin system in patients with active Crohn's disease.

BACKGROUND AND AIMS: Osteoporosis may occur in 25-30% of patients with Crohn's disease. Its pathogenesis is not completely understood. Both systemic inflammation in acute disease and treatment with systemic glucocorticoids have been implicated. The aim of the present study was to investigate changes in bone density and biochemical markers of bone metabolism before and during a 3-month period of high-dose glucocorticoid treatment for acute flare-up of Crohn's disease. METHODS: Twenty-five patients with active Crohn's disease requiring systemic glucocorticoid treatment (prednisolone, 60 mg/day) were investigated. Lumbar spine and femoral neck bone mineral densitometry was performed at baseline and again after 3 months. Clinical examinations including evaluation of the Crohn's disease activity index and measurement of the biochemical markers osteocalcin, deoxypyridinoline, osteoprotegerin and the soluble receptor activator of NF-kappaB ligand were performed prior to, and at 1, 2 and 12 weeks following steroid administration. RESULTS Median lumbar bone mineral density decreased significantly during the observation period by 1.04% from -0.84 (t score; range, -2.8 to +0.57) to -0.95 (range, -3.1 to +0.40; P = 0.022), while bone density of the total femur decreased by 2.9% from -0.83 (range, -2.61 to +1.86) to -0.90 (range, -2.65 to +0.19; P = 0.01). Serum levels of osteocalcin, a bone formation marker, and osteoprotegerin, an anti-resorptive cytokine produced by osteoblasts, decreased after the first 2 weeks of treatment and reached baseline levels after 3 months. No significant change was found for the bone resorption marker deoxypyridinoline, while soluble receptor activator of NF-kappaB ligand, a cytokine promoting bone resorption, tended to increase during steroid treatment. CONCLUSION: A decrease in bone mineral density in patients with Crohn's disease appears to result, at least in part, from a short-term effect of systemic glucocorticoid. Modulation of osteoclastogenesis by the receptor activator of NF-kappaB ligand/osteoprotegerin cytokine system and decreased osteoblastic function may be the underlying molecular basis.

Acute Disease↗
PubMed2002

Cyclosporine inhibits growth through the activating transcription factor/cAMP-responsive element-binding protein binding site in the cyclin D1 promoter.

The immunosuppressive agent cyclosporine affects proliferation depending on the cellular system used. In an attempt to study the inhibitory effect of cyclosporine on proliferation of pancreatic acinar cells, we used AR42J cells as a model system. Here we demonstrate that cyclosporine inhibits growth of these cells by inducing G(1) cell cycle arrest. This effect is mediated by the 5' regulatory region of the cyclin D1 gene and leads to a reduction of cyclin D1 mRNA expression and protein abundance. We show that in AR42J cells the proximal cyclin D1 promoter contains a cis-regulated element, which is important for the maintenance of basal transcriptional activity. This element overlaps the described cAMP-responsive element (CRE) and confers cyclosporine sensitivity to the cyclin D1 promoter. Furthermore, the DNA binding activity of the CRE-binding protein (CREB) decreases through cyclosporine treatment and this is mediated by cyclosporine-induced reduction of CREB steady-state levels. These results demonstrate that cyclosporine can inhibit proliferation of acinar cells by targeting the cyclin D1 promoter at the proximal CRE via a reduction of CREB protein abundance.

Animals↗
PubMed2002

Mechanism of activation of protein kinase D2(PKD2) by the CCK(B)/gastrin receptor.

Recently, we cloned a novel serine/threonine kinase termed protein kinase D2 (PKD2). PKD2 can be activated by phorbol esters both in vivo and in vitro but also by gastrin via the cholecystokinin/CCK(B) receptor in human gastric cancer cells stably transfected with the CCK(B)/gastrin receptor (AGS-B cells). Here we identify the mechanisms of gastrin-induced PKD2 activation in AGS-B cells. PKD2 phosphorylation in response to gastrin was rapid, reaching a maximum after 10 min of incubation. Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta. These PKCs are activated by gastrin in AGS-B cells. Thus, PKD2 is likely to be a novel downstream target of specific PKCs upon the stimulation of AGS-B cells with gastrin. Our data suggest a two-step mechanism of activation of PKD2 via endogenously produced diacylglycerol and the activation of PKCs.

Cell Line↗
PubMed2002

[Measurement of outpatient treatment costs of chronic inflammatory bowel diseases at a German university hospital].

OBJECTIVE: To create a concept for measuring and valuating resource utilization of outpatient treatment of patients with inflammatory bowel disease in a German university hospital. MATERIAL AND METHODS: The measurement of health services was achieved using a computer-based routinely administered data base of the Medical Department. Measuring costs was performed in three steps: 1. identification of the categories of resource utilization, 2. quantitative measurement of resource use, 3. monetary valuation of the utilization of resources using German fee schedules and prices for drugs. RESULTS: The resource utilization of 272 patients with a treatment period of more than 1 year could be identified in a structured form. Categories of resource use could be identified and quantitatively measured as follows: anamnesis and physical examination by a physician in 100% of the visits, laboratory tests in 87.1%, endoscopic or sonographic services in 36.9%, and radiologic procedures in 14.1%. In 93.6% of the visits a medication was prescribed. Annual costs of outpatient care provided by the hospital were 3,171 [symbol: see text] per patient. Medication accounted for 85% of total costs. Analyzing the costs of medical treatment, mesalazine was the major cost component (48%), followed by budesonide (15%). CONCLUSION: The presented concept offers a good access to measure costs of outpatient treatment of patients with inflammatory bowel disease. It is suitable for measuring costs in the economic evaluation of alternative treatments or diagnostic strategies in an outpatient setting. It furthermore may be used as a component in cost-of-illness studies. For transferring the concept to other hospitals, the availability of a routine documentation of services should be checked. For economic analysis, a further data management is required.

Adult↗
PubMed2002

Enteric nervous plasticity and development: dependence on neurotrophic factors.

The enteric nervous system in the mammalian gut is histologically and to some extent functionally similar to the central nervous system. Thus, structural and functional similarities between these systems are evident. As shown for the central nervous system, differentiation of neural crest-derived precursor cells of the enteric nervous system also depends essentially on different neurotrophic factors. Moreover, recent studies have revealed that these trophic factors also play a critical role throughout life by regulating neurotransmitter and neuropeptide synthesis, and by influencing neuronal morphology and synaptic functions. Consequently, our understanding of these complex interactions of the enteric nervous system and neurotrophic factors requires synergistic efforts from neurophysiology, biochemistry, and pharmacology in order to understand the complex phenomena of enteric nervous development and plasticity in the gut. Knowledge of these mechanisms might help to develop strategies for therapy of neuronal abnormalities, which cause different gastrointestinal diseases.

Animals↗
PubMed2002

Molecular mechanisms of sulfasalazine-induced T-cell apoptosis.

Impaired apoptosis of T-lymphocytes is involved in the development of chronic inflammatory disorders. Previously we have shown that the anti-inflammatory drug sulfasalazine induces apoptosis in a murine T-lymphocyte cell line. The aims of the present study were to expand these observations to human systems and to analyse the molecular basis for sulfasalazine-induced apoptosis. Sulfasalazine induces apoptosis both in Jurkat cells, a human T-leukaemia cell line (ED50 value approximately 1.0 mM), and in primary human peripheral blood T-lymphocytes (ED50 value approximately 0.5 mM). In contrast SW620 colon carcinoma cells or primary human synoviocytes are not affected at these concentrations suggesting a cell type-specific sensitivity to sulfasalazine. Sulfasalazine triggers the mitochondrial accumulation of Bax and induces a collapse of the mitochondrial transmembrane potential (deltapsi(m)). Sulfasalazine causes cytochrome c release from mitochondria and subsequent activation of caspase-3 and downstream substrates. However, the pan-caspase inhibitor Z-VAD.fmk fails to inhibit sulfasalazine-induced apoptosis. Sulfasalazine stimulates mitochondrio-nuclear translocation of the novel apoptogenic factor apoptosis-inducing factor (AIF) and triggers large-scale DNA fragmentation, a characteristic feature of AIF-mediated apoptosis. Sulfasalazine-induced DeltaPsi(m) loss, AIF redistribution, and cell death are fully prevented by overexpression of Bcl-2. In conclusion, our data suggest that sulfasalazine-induced apoptosis of T-lymphocytes is mediated by mitochondrio-nuclear translocation of AIF and occurs in a caspase-independent fashion. Sulfasalazine-induced apoptosis by AIF and subsequent clearance of T-lymphocytes might thus provide the molecular basis for the beneficial therapeutic effects of sulfasalazine in the treatment of chronic inflammatory diseases.

Apoptosis↗
PubMed2002

Transgenic overexpression of amphiregulin induces a mitogenic response selectively in pancreatic duct cells.

BACKGROUND & AIMS: The epidermal growth factor (EGF) receptor family and the corresponding ligands are frequently overexpressed in pancreatic cancer. To compare the biological effects of transforming growth factor (TGF)-alpha and amphiregulin (AR) on growth and differentiation of the exocrine pancreas, we have generated transgenic mice overexpressing AR under control of the elastase promoter. METHODS: Two independently generated transgenic mouse lines overexpress 50-, 43-, 28-, 26-, and 16-kilodalton AR forms in the pancreas. RESULTS: Morphologic and immunohistochemical examinations suggest that small intralobular duct and centro-acinar cells proliferate in response to AR in these mice. AR transgenic mice display increased Ras, Erk1/2, cyclin D/CDK4, and cyclin E/CDK2 activity and G1/S progression in pancreatic duct cells. In contrast to TGF-alpha transgenic mice, AR neither induced tubular complex formation nor elicited a strong fibrogenic response. AR induced a slight induction of ErbB2 on duct cells, whereas TGF-alpha resulted in overexpression of the EGF receptor in cells within tubular complexes. Furthermore, AR and TGF-alpha displayed different effects on differentiation of isolated acini in vitro comparable to the situation in vivo. CONCLUSIONS: These data suggest that AR induces a mitogenic response selectively in small duct cells through activation of Ras, CDK2, and CDK4, respectively. The closely related EGF receptor ligands, AR and TGF-alpha, display different biological effects when overexpressed in the exocrine pancreas in vivo.

Amphiregulin↗
PubMed2002

Abnormal organogenesis of Peyer's patches in mice deficient for NF-kappaB1, NF-kappaB2, and Bcl-3.

BACKGROUND & AIMS: Nuclear factor (NF) kappaB1, NF-kappaB2, and Bcl-3 encode for proteins of the NF-kappaB/Rel/IkappaB families, known as regulators of innate and adoptive immune responses. Targeted disruption of these genes showed essential roles in lymphoid organ development and organization. METHODS: NF-kappaB1-, NF-kappaB2-, and Bcl-3-deficient mouse lines were established, and their role in organogenesis of Peyer's patches (PP) was investigated. RESULTS: Macroscopic inspection showed a reduced number and size of PP in Bcl-3(-/-) and NF-kappaB1(-/-) mice but failed to detect PP in NF-kappaB2(-/-) mice. Whole-mount in situ hybridization revealed the presence of interleukin-7 receptor-alpha spots in NF-kappaB2(-/-) mice, indicating no defect in PP organogenesis of NF-kappaB2(-/-) mice in principle. Immunostaining shows that residual lymphocytes mainly consist of T cells. B cells are substantially reduced and are accumulated as terminal extravasations. Organized follicular structures and follicular dendritic cell networks fail to form, and myeloid, but not lymphoid, dendritic cells are obviously reduced. Expression of the chemokines macrophage inflammatory protein-3alpha, B-lymphocyte chemoattractant, and thymus-expressed chemokine is impaired in epithelial cells and in the subendothelial dome area that is not well defined. A similar but less severe phenotype is seen in Bcl-3(-/-) mice, which also do not develop germinal centers. In contrast, in NF-kappaB1(-/-) mice, T-cell numbers are visibly reduced, and no alteration could be observed in the B-cell and dendritic-cell populations. CONCLUSIONS: These data show that all 3 genes are crucial for PP development but contribute differently to PP organogenesis.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Stat3 and NF-kappaB activation prevents apoptosis in pancreatic carcinogenesis.

BACKGROUND & AIMS: Human pancreatic adenocarcinoma has an overall poor prognosis. Therapeutic efforts are often ineffective because of late diagnosis and a high degree of chemoresistance. Overexpression of transforming growth factor alpha in the pancreas of transgenic mice causes the formation of premalignant ductal lesions and the development of invasive ductal adenocarcinoma. The aim of the present study was to explore regulation of proapoptotic and antiapoptotic signals during pancreatic tumor development in mice. METHODS: EL-TGFalpha-hGH transgenic mice crossbred to p53-deficient mice develop ductal pancreatic adenocarcinoma resembling the human disease. During the multistep carcinogenesis up-regulation of Bcl-x(L) is evident early and persists throughout tumorigenesis as detected by Real Time PCR, Western blot analysis, and immunofluorescence. RESULTS: Up-regulation of Bcl-x(L) is evident early in tumor development and persists throughout tumorigenesis. The transcription factors Stat3 and NF-kappaB induce increased Bcl-x(L) expression in the premalignant lesions and tumor cells. Inhibition of either transcription factor alone leads to Bcl-x(L) down-regulation in transient transfection assays. Functional analysis shows that blocking of both Stat3 and NF-kappaB together induces programmed cell death in murine pancreatic tumor cells. CONCLUSIONS: These findings indicate that apoptosis resistance precedes formation of invasive pancreatic cancer. Therefore, combined inhibition of Stat3 and NF-kappaB might represent a novel strategy for tumor prevention and therapy.

Animals↗