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Helmut Friess

Publications and source records attributed to Helmut Friess.

At least 73 records · Page 4Linked to original sources
PubMed2003

Up-regulation of p75 neurotrophin receptor (p75NTR) is associated with apoptosis in chronic pancreatitis.

Activation of apoptosis in chronic pancreatitis has been demonstrated. The low-affinity neurotrophin receptor p75 (p75NTR) mediates apoptosis in many cell types in vivo and in vitro. The aim of this study was to examine whether p75NTR is involved in the apoptotic process in chronic pancreatitis. The quantity and localization of the receptor was evaluated using northern blot analysis, in situ hybridization, immunohistochemistry, and western blot analysis. Apoptosis was determined by TUNEL assay. By northern blot analysis, p75NTR mRNA levels were increased 40-fold in chronic pancreatitis compared with normal pancreas (P < 0.01). In situ hybridization revealed weak p75NTR mRNA expression in some ductal cells in the normal pancreas. In contrast in chronic pancreatitis moderate p75NTR expression was present in acinar cells next to fibrosis, ductal cells, and cells of ductular structures as well as in some islet cells. Immunostaining of p75NTR in normal pancreas and chronic pancreatitis tissue samples showed a similar intensity and distribution pattern as found by in situ hybridization. Higher p75NTR protein levels could be confirmed by western blot analysis, which revealed an 8.6-fold increase of p75NTR in chronic pancreatitis. TUNEL staining showed, in chronic pancreatitis samples, positivity in some acinar cells next to fibrosis, some ductal cells, and cells of ductular structures. Also some islet cells were positive by TUNEL staining. The presence of p75NTR immunoreactivity was positively correlated (P < 0.05) with the apoptotic index in the exocrine and endocrine pancreas. In conclusion, p75NTR, the low-affinity receptor of neurotrophins which mediates apoptosis, is up-regulated in CP and is involved in the apoptotic process of the exocrine and endocrine pancreas.

Adolescent↗
PubMed2003

Up-regulation, nuclear import, and tumor growth stimulation of the adhesion protein p120 in pancreatic cancer.

BACKGROUND & AIMS: Cell adhesion proteins have been implicated as tumor suppressors because they prevent malignant cells from dissociating their cell contacts. We have studied the role of p120(ctn), a recently discovered member of the cadherin/catenin family, in human pancreatic cancer. METHODS: In 32 resection specimens of pancreatic adenocarcinoma and 10 control samples the expression of p120(ctn) was studied by Northern blot, immunocytochemistry, and immunogold electron microscopy. Patient survival data, tumor grading, and staging were correlated to the experimental results. In PaTu 8889 T pancreatic cancer cells, p120(ctn) expression was suppressed with 21-nucleotide small interfering RNA (siRNA) duplexes and proliferation was determined by bromodeoxyuridine (BrdU) incorporation. RESULTS: In pancreatic cancer p120(ctn) messenger RNA (mRNA) was increased 3- to 4-fold. Although p120(ctn) was localized exclusively at cell contacts in controls it was found in the cytosol and nucleus of pancreatic cancer cells. This redistribution correlated to the degree of tumor dedifferentiation but was independent of tumor stage. The mean survival of patients with predominant membrane localization of p120(ctn) was 24 +/- 7 (SEM) months vs. 9 +/- 2 months for patients with predominant cytoplasmic p120(ctn) expression (P < 0.05). Silencing of p120(ctn) with siRNA duplexes reduced pancreatic cancer cell growth by 40%. CONCLUSIONS: Up-regulation, cytoplasmic redistribution, and nuclear import of p120(ctn) are associated with a more malignant phenotype of pancreatic cancer. This study further represents conclusive evidence for a direct involvement of p120(ctn) in malignant tumor cell proliferation. Both p120(ctn)-defective tumor cell contacts and p120(ctn)-mediated growth signals appear to contribute to the aggressive spread of pancreatic cancer.

Active Transport, Cell Nucleus↗
PubMed2003

Computational dissection of tissue contamination for identification of colon cancer-specific expression profiles.

Microarray profiles of bulk tumor tissues reflect gene expression corresponding to malignant cells as well as to many different types of contaminating normal cells. In this report, we assess the feasibility of querying baseline multitissue transcriptome databases to dissect disease-specific genes. Using colon cancer as a model tumor, we show that the application of Boolean operators (AND, OR, BUTNOT) for database searches leads to genes with expression patterns of interest. The BUTNOT operator for example allows the assignment of "expression signatures" to normal tissue specimens. These expression signatures were then used to computationally identify contaminating cells within conventionally dissected tissue specimens. The combination of several logic operators together with an expression database based on multiple human tissue specimens can resolve the problem of tissue contamination, revealing novel cancer-specific gene expression. Several markers, previously not known to be colon cancer associated, are provided.

Colon↗
PubMed2003

Hypoxia-inducible factor 1 regulates vascular endothelial growth factor expression in human pancreatic cancer.

INTRODUCTION: The microenvironment of low oxygen that is present in human pancreatic cancer in vivo may actively influence tumor growth as well as neovascularization. AIMS: To determine whether hypoxia-inducible factor 1 (HIF-1) is specifically activated by hypoxia in vitro in pancreatic cancer cells and correlated these findings with tumor specimens. METHODOLOGY: Hypoxic regulation of vascular endothelial growth factor (VEGF) was studied by northern blot analysis and enzyme-linked immunosorbent assay. Electrophoretic mobility shift assays and western blot analysis were used to demonstrate hypoxic activation of HIF-1. The relationship between HIF-1 and VEGF in human pancreatic cancer specimens was studied by immunohistochemical analysis, northern blot analysis, and in situ hybridization. RESULTS: Studies in vivo of human pancreatic cancer tissue showed co-localization of VEGF mRNA, which is produced in ductal cancer cells, and HIF-1alpha protein, which was detectable in cell nuclei of the same cells. HIF-1alpha mRNA expression was dramatically upregulated (approximately 13-fold) in these specimens as well. In vitro, all pancreatic cancer cell lines increased VEGF production when exposed to low oxygen levels, by highly specific activation of HIF-1 DNA binding activity to the VEGF promoter. Cancer cell lines with high constitutive levels of HIF-1alpha protein were found to produce higher basal levels of VEGF. CONCLUSION: We conclude that HIF-1 is the regulatory link between tumor hypoxia and VEGF production in pancreatic cancer, thus establishing a biochemical pathway between tumor hypoxia and neoangiogenesis in this highly aggressive neoplasm.

Adenocarcinoma↗
PubMed2003

Impaired insulin action on phosphatidylinositol 3-kinase activity and glucose transport in skeletal muscle of pancreatic cancer patients.

INTRODUCTION: Glucose intolerance or overt diabetes occurs in 80% of patients with pancreatic cancer (PC). This associated metabolic disorder includes peripheral insulin resistance, which may be caused by factors produced by the PC. The mechanism underlying PC-associated insulin resistance has not been clearly defined. AIM: To characterize basal and insulin-stimulated glucose transport, phosphatidylinositol (PI) 3-kinase activity, and glucose transporter 4 (GLUT4) in skeletal muscles of PC patients. METHODOLOGY: Skeletal muscle samples were obtained from the abdominal wall of 17 PC patients during surgery. Control muscles were sampled in the same way from 11 donors undergoing abdominal surgery for benign diseases. PI 3-kinase activity, glucose transport, and GLUT4 were assessed in vitro in these muscles. RESULTS: In the presence of physiologic concentrations of insulin, glucose transport and PI 3-kinase activity were significantly decreased in the PC group compared with controls. At supraphysiologic insulin concentrations, glucose transport was significantly decreased but PI 3-kinase activity was normalized. In the absence of insulin, these parameters were not significantly different between PC and control groups. Muscle GLUT4 contents were similar between PC and control groups. CONCLUSION: Defects in insulin-mediated PI 3-kinase activity and glucose transport contribute to the insulin resistance in patients with PC.

3-O-Methylglucose↗
PubMed2003

Prevention of metastatic pancreatic cancer growth in vivo by induction of apoptosis with genistein, a naturally occurring isoflavonoid.

INTRODUCTION: The critical need for novel therapeutic approaches to pancreatic cancer treatment is clear. Genistein, a naturally occurring isoflavonoid, is active against certain solid malignancies, but its effect on pancreatic cancer is unknown. AIMS: To investigate the bioactivity of genistein in experimental pancreatic cancer in vitro and in vivo. METHODOLOGY: The effect of intraperitoneal genistein administration on local tumor growth and metastatic disease was determined in an orthotopic nude mouse model. Apoptosis in tumor specimens was determined by the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) technique. In vitro, the effect of genistein on cell growth was assessed by cell count and MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) colorimetric assay. Apoptosis was determined in vitro by DNA laddering and annexin-V. Caspase-3 and nuclear factor-kappaB activity were measured following genistein treatment. RESULTS: In vivo, genistein significantly improved survival, almost completely inhibited metastasis, and increased apoptosis in an orthotopic model of pancreatic cancer. In vitro genistein treatment resulted in apoptosis in all pancreatic cancer cell lines tested, and this appeared to be mediated by activation of caspase-3. CONCLUSION: These findings suggest that the antimetastatic effect of genistein treatment in vivo is mediated by induction of apoptosis. Genistein may have a therapeutic benefit for patients with pancreatic cancer, in particular after surgery, to prevent recurrence of metastatic disease.

Animals↗
PubMed2003

Neurokinin-1 receptor expression and its potential effects on tumor growth in human pancreatic cancer.

The neurokinin-1 receptor (NK-1R) and its ligand substance P (SP) are involved in the pathogenesis of certain neural tumors. Because nerves are significantly altered in pancreatic cancer, evidence for alteration of this pathway in human pancreatic cancer was sought. Expression of NK-1R was analyzed by real-time quantitative RT-PCR, in situ hybridization, immunohistochemistry, and Western blot analysis in normal human pancreatic and pancreatic cancer tissue samples and in pancreatic cancer cell lines. Furthermore, the influence of SP analogs and of the NK-1R antagonist MEN 11467 on pancreatic cancer cell growth was analyzed by sulforhodamine B (SRB) assay. By real-time quantitative RT-PCR, NK-1R mRNA was increased 36.7-fold (p < 0.001) in human pancreatic cancer samples compared with normal controls. Enhanced NK-1R expression levels were not related to tumor grade but were associated with advanced tumor stage and poorer prognosis. By in situ hybridization and immunohistochemistry, NK-1R mRNA and immunoreactivity were only occasionally weakly present in acinar and ductal cells in the normal pancreas. In contrast, moderate to strong NK-1R mRNA signals and immunoreactivity were present in most cancer cells. By Western blot analysis, NK-1R was increased 26-fold (p < 0.01) in pancreatic cancer samples in comparison to normal controls. NK-1R mRNA was detected in five pancreatic cancer cell lines by real-time quantitative RT-PCR, with the highest levels in CAPAN-1 cells and the lowest in ASPC-1 cells. SP analogs stimulated pancreatic cancer cell growth, depending on the NK-1R expression level, and this effect could be blocked by a selective NK-1R antagonist. These findings illustrate that the NK-1R pathway is activated in human pancreatic cancer and has the potential to contribute to cancer cell growth, thus suggesting the existence of a neuro-cancer cell interaction in vivo.

Blotting, Western↗
PubMed2003

Origin and development of the precursor lesions in experimental pancreatic cancer in rats.

Notwithstanding the importance of understanding how pancreatic ductal adenocarcinoma develops, the process remains controversial. A key question is whether the cells of origin of the tubular complexes that constitute precursor lesions are derived from a single cell type or from multiple types. Suggestions that they arise solely from centroacinar cells or ductal cells have been based on inference due to their morphologic appearance in tissue from patients or investigation of limited numbers of tubular complexes in animal models later in the carcinogenic process. The present study establishes clearly that two steps are involved; rapid transdifferentiation to produce tubular complexes followed later by transformation of the component cells. Animals were killed at intervals beginning 1 day after implantation of the carcinogen dimethylbenzanthracene. Transdifferentiation of acinar cells to ductal cells does not require cell division. Transition of lobules to tubular complexes begins by 2 days after implantation of carcinogen. Within 4 days after implantation well-developed tubular complexes are present. Islets participate in the process. Ductal adenocarcinoma is observed by 1 month after implantation of carcinogen. Chymotrypsin and cytokeratin localized by immunocytochemistry indicate acinar and ductal cell characteristics. Acino-ductal transdifferentiation persists in carcinogen-implanted animals, but not in controls implanted with sodium chloride crystals or subjected to sham implantation. The precursor lesions (tubular complexes) are formed by the transdifferentiation of acinar cells and to a lesser extent islet cells, with the incorporation of the duct cells pre-existing in the lobules. Therefore, cells that at one time were acinar cells, islet cells, and duct cells, provide the precursor cells for the ductal adenocarcinoma that develops from tubular complexes. The results raise the question whether the transdifferentiated cells in the tubular complexes of patients with chronic pancreatitis are more susceptible to carcinogenic influences, resulting in the increased rate of pancreatic cancer.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2003

Relationship between overexpression of NK-1R, NK-2R and intestinal mucosal damage in acute necrotizing pancreatitis.

AIM: To study the expression of neurokinin-1 receptor (NK-1R) and neurokinin-2 receptor (NK-2R) in distal ileum of acute necrotizing pancreatitis (ANP) and to evaluate the relationship between expression of these two receptors and intestinal mucosal damage. METHODS: A total of 130 adult Sprague-Dawley rats were randomly divided into two groups: the rats in ANP group (n=80) were induced by the retrograde intraductal infusion of 30 g.L(-1) sodium taurocholate. And the rats in normal control group (n=50) received laparotomy only. Sacrifices were made 6 h, 12 h, 24 h and 48 h later in ANP and normal control group after induction respectively. Intestinal mucosal permeability was studied by intrajejunal injection of 1.5 mCi radioactive isotope (99m)Tc-diethlene triamine pentacetic acid (DTPA) and the radioactivity of (99m)Tc-DTPA content in urine was measured 6 h, 12 h, 24 h and 48 h after induction. Then the pancreas and intestine were prepared for pathology. Reverse transcription polymerase chain reaction (RT-PCR) was used to determine the mRNA expression of NK-1R and NK-2R, and Western blot was used to investigate the protein level of NK-1R and NK-2R. RESULTS: In ANP rats, serious histologic damages in intestinal mucosa were observed, and the radioactivity of (99m)Tc-DTPA in urine increased significantly in the ANP group. RT-PCR revealed that NK-1R and NK-2R mRNA level was overexpressed in the distal ileum of ANP as compared with the normal control group. Western blot discovered stronger NK-1R (14-fold increase) and NK-2R (9-fold increase) immunoreactivity in the intestinal mucosa of ANP rats. Moreover, the overexpression of NK-1R was associated with mucosal pathological score (r=0.77, P<0.01) and intestinal permeability (r=0.68, P<0.01) in ANP rats. CONCLUSION: NK-1R and NK-2R contribute to disrupted neuropeptides loop balance, deteriorate intestinal damage, and are involved in pathophysiological changes in ANP.

Amylases↗
PubMed2003

Gene-expression analysis of single cells-nested polymerase chain reaction after laser microdissection.

AIM: The structural and functional characteristics of cells are dependent on the specific gene expression profile. The ability to study and compare gene expression at the cellular level will therefore provide valuable insights into cell physiology and pathophysiology. METHODS: Individual cells were isolated from frozen colon tissue sections using laser microdissection. DNA as well as RNA were extracted, and total RNA was reversely transcribed to complementary DNA (cDNA). Both DNA and cDNA were analyzed by nested polymerase chain reaction (PCR). The quality of isolated DNA and RNA was satisfactory. RESULTS: Single cells were successfully microdissected using an ultraviolet laser micromanipulator. Nested PCR amplification products of DNA and cDNA of single cells could clearly be visualized by agarose gel electrophoresis. CONCLUSION: The combined use of laser microdissection and nested-PCR provides an opportunity to analyze gene expression in single cells. This method allows the analysis and identification of specific genes which are involved in physiological and pathophysiological processes in a complex of variable cell phenotypes.

Colon↗
PubMed2003

[Gene expression analysis in liver tissue at a single cell level by nested polymerase chain reaction and laser microdissection].

OBJECTIVE: To investigate the measurements of gene expressing at a single hepatocyte level. METHODS: Individual hepatocyte was isolated from cryostat tissue section using laser microdissection technique. To detect the mRNA expressed by single hepatocyte, RNA was extracted, reversely transcribed to cDNA and amplified by nested polymerase chain reaction (PCR). RESULTS: Single cell was microdissected from cryostat tissue using an ultraviolet laser micromanipulator. The RNA could be extracted from the isolated cell(s), and the RT-PCR production could be observed after electrophoresis, whose quantitation was compatible with the number of cells. CONCLUSION: Combining laser microdissection and nested RT-PCR can monitor gene expression at a single cell level in vivo.

Dissection↗
PubMed2003

Overexpression of oncogenic STK15/BTAK/Aurora A kinase in human pancreatic cancer.

PURPOSE: Multiple chromosome abnormalities, including gain of chromosome20q, have been detected frequently in human pancreatic cancers. Overexpression of the STK15/BTAK/Aurora A gene located on chromosome 20q13, which encodes a centrosome-associated serine/threonine kinase, has been shown to induce chromosomal instability, leading to aneuploidy and cell transformation in multiple in vitro experimental systems. The purpose of this study was to investigate the expression and copy number alteration of STK15 in pancreatic cancer. EXPERIMENTAL DESIGN: STK15 expression at both the mRNA and protein levels together with the copy number of STK15 gene was measured in nine pancreatic carcinoma cell lines: (a) HPAF-II; (b) Aspc-1; (c) Panc-1; (d) Panc-3; (e) Panc-28; (f) Panc-48; (g) HS766T; (h) MIAPaCa-2; and (i) BxPc3. STK15 protein expression was also examined in normal pancreatic tissues and tumors by Western blotting and immunohistochemistry. RESULTS: STK15 was overexpressed in all of the nine cell lines examined, but gene amplification was infrequent. Western Blot analysis of primary tumor tissues revealed 2-10 times overexpression of STK15 protein compared with normal adjacent tissues from pancreatic cancer patients. Concurrent overexpression of cdc20, an STK15-associated protein, and reduced expression of cdc25, a mitosis-activating protein phosphatase, were detected in the same tumor samples. Elevated STK15 protein expression was detected in 22 of 38 tumor sections (58%) from pancreatic cancer patients. The extent of STK15 expression was not significantly correlated with the size, degree of differentiation, and metastasis status of the tumors. CONCLUSIONS: These results show that STK15 is overexpressed in pancreatic tumors and carcinoma cell lines and suggest that overexpression of STK15 may play a role in pancreatic carcinogenesis.

Aged↗
PubMed2003

[Preferential expression of cartilage oligomeric matrix protein in degenerating acinar cells in chronic pancreatitis and in chronic pancreatitis-like lesions].

OBJECTIVES: To study cartilage oligomeric matrix protein (COMP) mRNA and protein expression in normal pancreas, chronic pancreatitis (CP), and pancreatic cancer tissues. METHODS: Tissues from 15 cases of normal pancreas, 14 cases of chronic pancreatitis and 14 cases of pancreatic cancer were analyzed by Northern blot, Western blot, in situ hybridization and immunohistochemistry. RESULTS: COMP mRNA signals and immunoreactivity were strongly present in the cytoplasm of degenerating acinar cells in CP tissues as well as in CP-like lesions in pancreatic cancer tissues. In contrast, COMP expression was weak to absent in the cytoplasm of cancer cells in pancreatic cancer tissues, and in ductal cells and islet cells in normal pancreatic tissues. CONCLUSION: COMP is preferentially expressed in degenerating acinar cells in CP and in CP-like areas in pancreatic cancer, suggesting a potential role of this molecular in acinar cell dysfunction in CP.

Blotting, Northern↗
PubMed2002

Splenic tissue autotransplantation in rabbits: no restoration of host defense.

BACKGROUND: The loss of spleen may increase the incidence of overwhelming sepsis. To prevent this, splenic autotransplantation has been performed in humans and experimental animals. However, there is still controversy about the effectiveness of regenerated splenic tissue in preventing infection. This study explored the effectiveness of splenic tissue autotransplantation in restoring host defense. MATERIALS AND METHODS: Rabbits were divided into three groups: splenic autotransplantation, sham operation, and total splenectomy. Histomorphology, T-lymphocyte count, serum lysozyme levels, hemolysin titers, and pneumococcal clearance were observed as read-out parameters over 24 weeks. RESULTS: Histological study showed that the white pulp was poorly developed and central arterioles were missing in the regenerated splenic tissue of the autotransplanted rabbits. The weight of regenerated spleens recovered 6 months later in the splenic autotransplantation group was 11% of that in the sham operation group and was significantly less than the weight at implantation. There was no significant difference in the number of T lymphocytes or level of serum lysozyme between the three groups. A poor antibody response by the rabbits in the splenic autotransplantation and total splenectomy groups was noted after the primary intravenous administration of sheep red blood cells compared to those of sham operation group. After the challenge with type 3 pneumococci intravenously, pneumococcal clearance from the bloodstream in the splenic autotransplantation group did not differ significantly from that in the total splenectomy group, but was markedly delayed compared with that in the sham operation group. CONCLUSIONS: The low quantity and poor quality of the regenerated splenic tissue contribute to the inferior immunoprotective ability of animals autotransplanted with one-third of the original spleen. This suggests that the regenerated spleen cannot compensate for the immunological function of the original one, especially host resistance to infection.

Animals↗
PubMed2002

Induction and expression of betaig-h3 in pancreatic cancer cells.

betaig-h3 (TGFBI, keratoepithelin) was first identified as a transforming growth factor-beta1 (TGF-beta1)-inducible gene in a human lung adenocarcinoma cell line. It encodes for a secreted extracellular matrix (ECM) protein, which is thought to act on cell attachment and ECM composition. Mutations of the betaig-h3 gene are involved in several corneal dystrophies. Pancreatic cancers display multiple alterations in the TGF-beta signaling pathway and in TGF-beta response genes, such as overexpression of all three TGF-beta isoforms and Smad4 mutations. In this report, we determined that betaig-h3 mRNA levels were induced by TGF-beta1 in two out of five examined pancreatic cancer cell lines (CAPAN-1, PANC-1). In CAPAN-1 cells, which harbor a Smad4 mutation, betaig-h3 but not PAI-1 was induced by TGF-beta1, whereas in PANC-1 cells that express wild-type Smad4, TGF-beta1 induced both PAI-1 and betaig-h3. In human pancreatic tissues, there was a 32.4-fold increase in betaig-h3 mRNA levels in pancreatic cancers in comparison to normal control tissues. In situ hybridization analysis revealed that betaig-h3 mRNA was expressed mainly in the cancer cells within the pancreatic tumor mass. These findings suggest that betaig-h3 is induced by TGF-betas in pancreatic cancer cells even in the presence of Smad4 mutations, which might explain, in part, the increased betaig-h3 mRNA levels observed in pancreatic cancer cells in vivo.

Adolescent↗
PubMed2002

Increased arylhydrocarbon receptor expression offers a potential therapeutic target for pancreatic cancer.

The arylhydrocarbon receptor (AhR) was initially identified as a member of the adaptive metabolic and toxic response pathway to polycyclic aromatic hydrocarbons and to halogenated dibenzo-p-dioxins and dibenzofurans. In the present study, we sought to determine the functional significance of the AhR pathway in pancreatic carcinogenesis. AhR expression was analysed by Northern blotting. The exact site of AhR expression was analysed by in situ hybridization and immunohistochemistry. The effects of TCDD and four selective AhR agonists on pancreatic cancer cell lines were investigated by growth assays, apoptosis assays, and induction of the cyclin-dependent kinase inhibitor p21. There was strong AhR mRNA expression in 14 out of 15 pancreatic cancer samples, weak expression in chronic pancreatitis tissues, and faint expression in all normal pancreata. In pancreatic cancer tissues, AhR mRNA and protein expression were localized in the cytoplasm of pancreatic cancer cells. TCDD and the four AhR agonists inhibited pancreatic cancer cell growth in a dose-dependent manner, and decreased anchorage-independent cell growth. DAPI staining did not reveal nuclear fragmentation and CYP1A1 and was not induced by TCDD and AhR agonists. In contrast, TCDD and AhR agonists induced the expression of the cyclin-dependent kinase inhibitor p21. In conclusion, the relatively non-toxic AhR agonists caused growth inhibition in pancreatic cancer cells with high AhR expression levels via cell cycle arrest. In addition, almost all human pancreatic cancer tissues expressed this receptor at high levels, suggesting that these or related compounds may play a role in the therapy of pancreatic cancer in the future.

Adenocarcinoma↗
PubMed2002

Overexpression of Bax sensitizes human pancreatic cancer cells to apoptosis induced by chemotherapeutic agents.

PURPOSE: Bax plays an important role in the regulation of apoptosis induced by chemotherapy and other stimuli. We therefore investigated the role of Bax in drug-induced apoptosis in human pancreatic cancer cells. METHOD: A tetracycline-inducible retroviral expression vector bearing the human bax-alpha gene was constructed. ASPC-1 cells were stably infected with this vector. The sensitivity of the transformed cell line to gemcitabine and 5-Fu was assessed. RESULTS: Western blots revealed that Bax expression was enhanced in these cells by the tetracycline analogue doxycycline. Enhanced expression of Bax itself did not inhibit the growth rate of infected cells and did not influence expression of Bcl-2 and Bcl-xL. However, it significantly increased the sensitivity of cells to the chemotherapeutic drugs gemcitabine and 5-Fu. These drugs also activated caspase-8 and caspase-3 by up to ninefold. Caspase activation and/or an imbalance in Bax and Bcl-2/Bcl-xL expression may be the reasons for the augmentation of cytotoxicity by these drugs. CONCLUSIONS: The findings suggest that enhanced Bax expression may have therapeutic application in enhancing the efficacy of chemotherapy in pancreatic cancers.

Anti-Bacterial Agents↗