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PubMed2003

Effect of apoptogenic stimuli on colon carcinoma cell lines with a different c-myc expression level.

We have recently demonstrated that a high c-myc endogenous amplification level confers an apoptosis-prone phenotype to serum-deprived colon carcinoma SW613-S cells. The aim of this study was to gain new insights into the features of c-myc-dependent apoptosis, by extending our analysis to different apoptogenic stimuli. The study was carried out on clones, derived from the human colon carcinoma SW613-S cell line, which harbor different levels of endogenous c-myc amplification, and on isogenic cell lines with an enforced c-myc overexpression. Our results indicate that cells with endogenous or transfected exogenous c-myc overexpression (SW613-12A1 and -2G1mycP2Tu1 cell lines, respectively), activate the apoptotic machinery in response to the treatment with etoposide, doxorubicin and vitamin D3, which induce apoptosis through the death receptor Fas. The low levels of c-myc expression present in SW613-B3 and -B3mycC5, seem to be unable to activate Fas-mediated apoptosis, thus suggesting that only a high c-myc expression can bypass the lack of Fas receptor. Apoptosis induction mediated by DNA damage and long-term culture was independent of c-myc expression. A pathway of apoptosis characterized by the activation of the enzyme L-DNase II, was observed in both 12A1 and B3 cell lines.

Antineoplastic Agents↗
PubMed2004

Hepatocyte apoptosis, expression of death receptors, and activation of NF-kappaB in the liver of nonalcoholic and alcoholic steatohepatitis patients.

OBJECTIVES: The increasing incidence of nonalcoholic (NASH) and alcoholic steatohepatitis (ASH), associated with lack of effective treatment, has prompted intensive studies on disease pathogenesis. Apoptosis is recognized as common in liver injury and may also contribute to tissue inflammation, fibrogenesis, and development of cirrhosis. In this study, we identified mechanisms of apoptosis induction in human steatohepatitis, and evaluated potential associations between apoptosis, liver pathology, and clinical presentation in NASH and ASH. METHODS: Hepatocyte apoptosis was evaluated by the TUNEL assay in 20 patients with NASH (all ambulatory), 40 with ASH (20 ambulatory, 20 hospitalized), and 20 controls. Liver biopsies were also graded for inflammation and fibrosis. Immunohistochemistry was performed for death receptors (Fas and TNF-R1), activated caspase-3, NF-kappaB p65, antiapoptotic Bcl-2 protein, and uncoupling protein 2 (UCP-2). RESULTS: TUNEL-positive hepatocytes were markedly increased in NASH (p < 0.05) and ASH (p < 0.01). Similar results were obtained for activated caspase-3, confirming the occurrence of apoptosis. The Fas receptor was upregulated in ASH, especially in hospitalized patients (p < 0.01), whereas TNF-R1 was expressed both in NASH and ASH (p < 0.01). In addition, patients with ASH showed a remarkable expression of active NF-kappaB, as compared to NASH and controls (p < 0.01). Degrees of inflammation and fibrosis correlated with NF-kappaB p65 expression, which in turn coincided with apoptosis albeit Bcl-2 and UCP-2 expression. CONCLUSIONS: Liver injury in NASH and ASH is associated with increased hepatocyte apoptosis mediated by death receptors. Further, apoptosis correlates with active NF-kappaB expression, and disease severity. This potential mechanistic link might provide multiple interesting targets for therapeutic intervention.

Adult↗
PubMed1997

Apoptosis in autoimmune and non-autoimmune thyroid disease.

The elimination of autoreactive T cells in the thymus involves the process of programmed cell death. Animal model studies, using the lpr and gld strains of mice, have identified FAS receptor (FAS) and FAS ligand (FAS-L) as important components of this mechanism. Whether FAS and FAS-L are also implicated in the autoimmune destruction of a target organ, such as the thyroid, remain hypothetical. An accompanying paper in this issue has addressed the question by FACS and immunocytochemical analysis of FAS expression and apoptosis in thyrocytes grown in culture and in intact thyroid tissues obtained from Hashimoto's thyroiditis, multinodular goitre and Graves' disease. The overall results suggest that the degree of FAS expression on target cells may determine their sensitivity to T-cell mediated cytotoxicity in the absence of perforin or granzyme directed apoptosis mechanisms.

Animals↗
PubMed2000

Killing of Fas ligand-resistant renal carcioma cells by interleukin-2- and BCG-activated effector cells.

Activated cytolytic effector cells like lymphokine-activated killer (LAK) and the recently described bacillus-Calmette-Guerin-activated killer (BAK) cells are thought to mediate antitumor effects against metastatic renal cell carcinoma (RCC) and superficial bladder cancer respectively. Perforin and Fas ligand (FasL) have been described as the major lytic principles in cellular cytotoxicity. Using a radioactive-release assay and specific inhibitors, we investigated the molecular mechanisms used by LAK and BAK cells in the lysis of renal carcinoma cells. In addition, we evaluated the susceptibility of RCC cells to FasL-mediated cytotoxicity. LAK and BAK cells effectively lysed the renal cancer cell line SK-RC-35 upon cell-cell contact. Both effector cell populations were shown to produce perforin and FasL as determined by reverse transcriptase/polymerase chain reaction (RT-PCR). Using fluorescence-activated cell sorting analyses and RT-PCR, we detected a marked Fas receptor (Fas, CD95) expression on RCC cells. However, RCC cells were shown to be resistant to killing by recombinant FasL and lysis by BAK and LAK cells was not inhibited in the presence of anti-FasL antibody. In contrast, the cytotoxicity exerted by LAK and BAK cells was drastically reduced in the presence of the Ca2+-chelating agent EGTA as well as concanamycin A, a specific inhibitor of perforin-mediated lysis. These results demonstrate that cytolysis of FasL-resistant RCC cells by activated immune cells is mediated via perforin. Our findings give further insights into the molecular mechanisms involved in the elimination of RCC by cytotoxic lymphocytes activated with biological response modifiers.

Adjuvants, Immunologic↗
PubMedDate not supplied

Cells behaving badly: a theoretical model for the Fas/FasL system in tumour immunology.

One proposed mechanism of tumour escape from immune surveillance is tumour up-regulation of the cell surface ligand FasL, which can lead to apoptosis of Fas receptor (Fas) positive lymphocytes. Based upon this 'counterattack', we have developed a mathematical model involving tumour cell-lymphocyte interaction, cell surface expression of Fas/FasL, and their secreted soluble forms. The model predicts that (a) the production of soluble forms of Fas and FasL will lead to the down-regulation of the immune response; (b) matrix metalloproteinase (MMP) inactivation should lead to increased membrane FasL and result in a higher rate of Fas-mediated apoptosis for lymphocytes than for tumour cells. Recent studies on cancer patients lend support for these predictions. The clinical implications are two-fold. Firstly, the use of broad spectrum MMP inhibitors as anti-angiogenic agents may be compromised by their adverse effect on tumour FasL up-regulation. Also, Fas/FasL interactions may have an impact on the outcome of numerous ongoing immunotherapeutic trials since the final common pathway of all these approaches is the transduction of death signals within the tumour cell.

Apoptosis↗
PubMed2003

Sensitization of head and neck squamous cell carcinoma cells to Fas-mediated apoptosis by the inhibition of Bcl-X(L) expression.

BACKGROUND: Various types of malignant tumor cells are known to acquire resistance to Fas receptor (Fas)-mediated apoptosis. In Fas-sensitive cells, Fas-mediated apoptosis is observed when anti-Fas antibody is bound to Fas. Bcl-2 and Bcl-X(L) are representative anti-apoptosis proteins reported to be capable of suppressing Fas-mediated apoptosis. OBJECTIVE: To investigate the mechanism of resistance acquisition to Fas-mediated apoptosis in cultured human head and neck squamous cell carcinoma cells (HNSCCs). METHODS AND RESULTS: We applied an anti-Fas antibody (CH11) to Fas-expressing HNSCCs (HSC-2) and the CH11 did not induce cell death in HSC-2. Treatment with actinomycin D (ActD) converted the phenotypes of HSC-2 from CH11-resistant to CH11-sensitive. Western blot analysis showed no differences between ActD-treated and ActD-untreated HSC-2 in the expression of Bcl-2. On the other hand, the expression of Bcl-X(L) was greatly reduced in ActD-treated HSC-2. Moreover, the reduction of Bcl-X(L) by specific antisense oligonucleotide treatment enhanced the CH11-induced cell death of HSC-2. CONCLUSION: Our data suggest that Fas-signaling might be regulated by a Bcl-X(L)-inhibitable step in CH11-resistant HSC-2.

Antibodies, Monoclonal↗
PubMed1997

Expression of Fas-Fas ligand system associated with atresia in murine ovary.

We detected that Fas receptor (Fas) was expressed at transcriptional levels in oocytes/eggs and some granulosa cells of murine ovary, whereas, Fas ligand (FasL) was found to be strongly expressed in granulosa cells by means of in situ hybridisation. These results were supported by an indirect immunofluorescence (IIF) test with anti-Fas monoclonal antibody (mAb)/FasL Ab. The lysates from granulosa cells were precipitated by anti-FasL Ab, exhibiting a specific band at 40 kDa. When zona pellucida (ZP)-free eggs were incubated with granulosa cells in vitro, apoptosis (DNA fragmentation) was induced in the eggs, as detected by the terminal deoxynucleotide transferase mediated dUTP-nick end labelling (TUNEL) method. To examine whether FasL-bearing cells can induce apoptosis in eggs expressing Fas through molecular interaction between FasL and Fas, we employed a baculovirus expression system to generate FasL on the surface of Spodoptera frugiperda (Sf9) cells. The co-incubation of eggs with Autographa californica nuclear polyhedrosis virus (AcNPV) and FasL transfected Sf9 (Sf9-FasL) cells in vitro was performed and resulted in the induction of apoptosis in eggs as detected by the TUNEL method. Apoptosis was absent in eggs co-incubated with AcNPV-1393 transfected Sf9 (Sf9-1393) cells. Thus, ovarian atresia was suggested to be induced by molecular interaction between FasL on granulosa cells and Fas on oocytes/eggs during oogenesis.

Animals↗
PubMed2005

Nonoxynol-9 induces apoptosis of endometrial explants by both caspase-dependent and -independent apoptotic pathways.

Contraceptive microbicides formulated as vaginal gels offer the possibility of women-controlled contraception and prevention of HIV infection. The effects of these gels on the upper reproductive tract are largely unknown. The purpose of this study was to determine whether nonoxynol-9 (N-9) induces apoptosis in human endometrium using endometrial explant as a model. Apoptosis was determined by gel electrophoresis for the detection of DNA fragmentation and by immunohistochemistry using the M30 CytoDEATH and anti-cleaved caspase-3 (CASP3) antibodies for the detection of caspase activity. The ability of the broad-spectrum caspase inhibitor and CASP3-specific inhibitor to prevent N-9-induced cell death was measured. Expression of apoptosis-related genes such as BCL2, BAX, Fas receptor (FAS), and Fas ligand (FASLG) was quantified using real-time polymerase chain reaction (PCR) analysis. This study demonstrated that N-9 induced DNA fragmentation and caspase activity in endometrial explants in a dose- and time-dependent manner. Caspase inhibitors did not fully prevent the N-9-induced DNA fragmentation. Real-time PCR analysis revealed that FAS and FASLG were largely increased following N-9 treatment. Together, these results suggested that apoptosis triggered by N-9 in endometrial explants is mediated upstream via FAS and FASLG, followed by CASP3 activation leading to final cell death. It appears that other factors besides caspases are also involved in the N-9-induced apoptosis.

Adolescent↗
PubMed1999

Cryptosporidium parvum induces apoptosis in biliary epithelia by a Fas/Fas ligand-dependent mechanism.

Although the clinical features of sclerosing cholangitis from opportunistic infections of the biliary tree in patients with acquired immunodeficiency syndrome (AIDS) are well known, the mechanisms by which associated pathogens, such as Cryptosporidium parvum, cause disease are obscure. Using an in vitro model of biliary cryptosporidiosis, we observed that C. parvum induces apoptosis in cultured human biliary epithelia. Both caspase protease inhibitors and neutralizing antibodies to either Fas receptor (Fas) and Fas ligand (FasL) inhibited this process; neutralizing antibodies to other apoptotic cytokines [interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and transforming growth factor-beta (TGF-beta)] had no effect. C. parvum stimulated FasL membrane surface translocation, increased both FasL and Fas protein expression in infected biliary epithelia, and induced a marked increase of soluble FasL (but not IL-1beta, TNF-alpha, and TGF-beta) in supernatants from infected cells. When a coculture model is used in which infected and uninfected cell populations were physically separated by a semipermeable membrane, both uninfected biliary epithelia and uninfected Fas-sensitive Jurkat cells (but not a Fas-resistant Jurkat cell line) underwent apoptosis when cocultured with infected biliary epithelia. Moreover, both a neutralizing antibody to FasL and a metalloprotease inhibitor blocked the apoptosis in uninfected cocultured cells. Activation of caspase activity was also observed in uninfected cocultured biliary epithelia. The data suggest that C. parvum induces apoptosis in biliary epithelia by a Fas/FasL-dependent mechanism involving both autocrine and paracrine pathways. These observations may be relevant to both the pathogenesis and therapy of the cholangitis seen in AIDS patients with biliary cryptosporidiosis.

Animals↗
PubMed2000

[Resistance to Fas-mediated apoptosis in head and neck squamous cell carcinoma cells].

Various types of carcinoma cells have been shown to escape immune recognition by constitutive resistance to Fas receptor (Fas)-mediated apoptosis. The purpose of this study was to examine the sensitivity to Fas-mediated apoptosis of human head and neck squamous cell carcinoma (HNSCC) cells. We applied an anti-Fas monoclonal antibody (CH11) to HNSCC cell lines and monitored their cell death. All three HNSCC cell lines examined expressed Fas protein but not Fas-ligand mRNA. CH11 did not induce cell death (CH11-resistant) in any of the three HNSCC cell lines examined. Treatment with actinomycin D (ActD) converted the phenotypes of the CH11-resistant HNSCC cell lines from CH11-resistant to CH11-sensitive, suggesting that the resistance to CH11-induced apoptosis was dependent on RNA synthesis. Western blot analysis did not show any differences in expression of Bcl-2 between the non-treated and ActD-treated HNSCC cell lines. Expression of Bcl-XL, on the other hand, was greatly reduced in the ActD-treated HNSCC cell lines, implying that Fas signaling in the CH11-resistant HNSCC cell lines might be regulated by an Bcl-XL-inhibitable step.

Apoptosis↗
PubMed2000

FasL:Fas ratio--a prognostic factor in breast carcinomas.

Programmed cell death (apoptosis) is primarily mediated by Fas ligand (FasL; CD95L) and the Fas receptor (Fas; CD95). In this study, FasL was detected by immunohistochemical analysis in 85% of breast carcinomas and 14% of fibroadenomas randomly chosen, indicating that high expression of FasL might play a role in tumor pathology. FasL and Fas levels as well as FasL:Fas ratios were further ascertained in 215 human breast tumors, including 199 invasive ductal carcinomas, by real-time quantitative reverse transcription-PCR and compared with expression levels and ratios found in 25 normal human tissues, in 37 fibroadenomas, and in 5 normal breast tissues. Among breast carcinomas, high FasL mRNA expression seems to be positively correlated with histological grading (n = 212; P<0.0001). A ratio of FasL:Fas mRNA transcripts >1 is found to be significantly associated with decreased patient's disease-free survival (n = 211; P<0.03) and increased mortality (n = 211; P = 0.19). A FasL:Fas ratio >1 is related to tumor progression scored by histological grading (n = 212; P<0.02). The selection process leading to highly aggressive breast tumor variants might be enhanced by FasL-mediated tumor fratricide, eventually a possible target for novel therapeutic strategies.

Adolescent↗
PubMed2005

[The RT-PCR-identified Fas and FasL expression and apoptosis in mouse hepatoma MH-22a and histiocytic sarcoma J-774 clonal lines coupled with in vitro cultivation with syngenic splenocytes].

Malignant growth is associated with various patterns of interaction between tumor cells and those of the body immune system, interaction between Fas-receptor (Fas) and Fas-ligand (FasL) expression being one of them. These mechanisms were simulated in vitro using the main cell populations from murine hepatoma MH-22a, histiocytic sarcoma J-774 and their clonal lines obtained from cocultivation of tumor cells and syngenic splenocytes. Fas and FasL expression was identified by the RT-PCR method while apoptosis--by electrophoresis of low molecular DNA fractions and clonogenic survival.

Animals↗
PubMed1999

Resistance to Fas (APO-1/CD95)-mediated apoptosis and expression of Fas ligand in esophageal cancer: the Fas counterattack.

The mechanisms by which esophageal tumors escape immunologic recognition and clearance are only partly understood at the molecular level. Esophageal cancers have been shown to evade host recognition by down-regulation of antigen presentation and production of immunosuppressive factors. Recently, two independent reports have shown that esophageal tumor cells abundantly express Fas ligand (FasL) in vivo. As the triggering agonist for Fas receptor (Fas or APO-1/CD95)-mediated apoptosis of lymphocytes, FasL normally plays immune down-regulatory roles, including activation-induced cell death of T and B cells, as well as maintaining immune privilege in certain organs. Fas ligand expressed by esophageal cell lines has been shown to induce apoptosis of cocultured Fas-sensitive lymphoid cells in vitro. FasL expression by esophageal carcinomas in vivo has been associated with significantly reduced tumor-infiltrating lymphocytes (TILs) in FasL-positive tumor nests, concomitant with significantly increased TIL apoptosis in these nests. These studies support a 'Fas counterattack' mechanism of immune escape in esophageal cancer. By expressing functional Fas ligand, esophageal cancer cells can deplete antitumor lymphocytes by inducing apoptosis. To express functional FasL, esophageal carcinomas also acquire molecular mechanisms to resist autocrine Fas-mediated apoptosis of tumor cells.

Apoptosis↗
PubMed2005

FAS and FAS-L expression by tumor cells and lymphocytes in breast carcinomas and their lymph node metastases.

FAS receptor (FAS, CD95) and FAS ligand (FAS-L, CD95-L) are complementary members of a particular apoptotic pathway that plays a major role in immune regulation. The activation of FAS-L may trigger cytotoxic mechanisms leading to the death of FAS-expressing cells. Tumor cells and tumor-infiltrating lymphocytes (TIL) may express FAS and FAS-L in various proportions, and their interplay may affect tumor behavior. In the present study, we explored the expression of FAS and FAS-L in 28 mammary carcinomas (19 ductal and 9 lobular) and in their lymph node metastases. The expression of these mediators in immunostained sections was graded and evaluated comparatively between normal and neoplastic mammary epithelium, between tumor cells and TILs, and between mammary carcinoma cells and their lymph node metastases. We demonstrated the coexpression of FAS and FAS-L by breast carcinoma cells and TIL, with FAS expressed more strongly by normal epithelial cells and TIL than tumor cells. FAS-L was better stained on tumor cells than on TIL. There was equal or greater expression of FAS and FAS-L in the primary tumors and their TIL than in the metastatic counterparts. Comparing the expression of FAS with that of FAS-L, we recorded FAS equal or stronger than FAS-L in the primary mammary tumors and the reversal of their expression, FAS-L greater than FAS in the lymph node metastases. These results are consistent with reports of studies with other tumors, suggesting that the upregulated FAS-L indicates an increased ability of tumor cells to induce apoptosis in TIL and in the normal tissues invaded. However, it is understood that the FAS/FAS-L system, although essential for apoptosis, is only a contributing factor to the complex process of tumor invasion and antitumor defense.

Adult↗
PubMed2004

Upregulation of Fas/Fas ligand-mediated apoptosis by gossypol in an immortalized human alveolar lung cancer cell line.

Gossypol has wide antineoplastic effects in vitro, but its effects on human lung cancer have not been explored. To evaluate the activity of gossypol against alveolar cell lung cancer and to provide information on the mechanism of action, we examined the effects of gossypol on the proliferation of A549 cells indirectly using an XTT assay and on the distribution of cells within the phases of the cell cycle using flow cytometry. We also examined several factors that may affect apoptosis, including p53, p21/WAF1, Fas receptor, Fas ligand (FasL) and caspase 8 activity. The results showed that gossypol inhibited proliferation of A549 cells at a concentration of 0.5 micromol/L after 12 h treatment. The effect was both dose- and time-dependent by the induction of apoptosis without the effect of p53 and p21/WAF1. Upregulation of Fas/FasL, in association with the activation of downstream caspase 8 activity, was observed following treatment with gossypol. The Fas/FasL pathway accounted for 75% of gossypol-mediated apoptosis. We suggest that the Fas/FasL apoptotic system is the major pathway for gossypol-mediated apoptosis of A549 cells. Gossypol had no effect on the distribution of A549 cells within the phases of the cell cycle. In conclusion, gossypol inhibited A549 cells mainly by induction of the Fas/FasL apoptotic pathway, but not the p53 and p21/WAF1 pathway.

Apoptosis↗
PubMed2004

Fas and Fas ligand: Expression and soluble circulating levels in bile duct carcinoma.

Alteration of the Fas receptor (Fas)-/ligand (FasL) system including their soluble forms (sFas and sFasL) is thought to be one of the mechanisms preventing the immune system from rejecting the tumor cells. We investigated the tissue expression of Fas, FasL, and the alteration of sFas and sFasL in patients with bile duct carcinoma. Thirty-four samples were immunostained for Fas and FasL, and levels of sFas and sFasL in the serum of 62 patients were determined using an enzyme-linked immunoadsorbent assay. Patients with strongly positive Fas levels showed significantly better prognosis than those with weakly positive or negative Fas levels. The mean serum levels of sFas in healthy individuals were significantly higher in patients with carcinoma. However, the mean serum levels of sFasL were significantly lower in the patients with carcinoma. Serum levels of sFas and sFasL might be a significant and independent prognostic parameter in patients with bile duct carcinoma.

Adult↗
PubMed1996

Swapping between Fas and granulocyte colony-stimulating factor receptor.

Fas belongs to the tumor necrosis factor/nerve growth factor receptor family. The Fas ligand binds to its receptor, Fas, and induces apoptosis in Fas-bearing cells. The granulocyte colony-stimulating factor receptor (G-CSFR) is a member of the hemopoietic growth factor receptor family. G-CSF induces its dimerization and regulates the proliferation and differentiation of neutrophilic granulocytes. We constructed hybrid receptors between Fas and G-CSFR and expressed them in the mouse T cell line WR19L or the mouse myeloid interleukin-3-dependent FDC-P1 cell line. The Fas ligand or an agonistic anti-Fas antibody stimulated proliferation of the FDC-P1 transformants expressing a chimera consisting of the Fas extracellular and G-CSFR cytoplasmic regions. On the other hand, G-CSF could not induce apoptosis in the transformants expressing the chimera consisting of the G-CSFR extracellular and Fas cytoplasmic regions, but these cells were killed by a polyclonal antibody against G-CSFR. These results indicated that receptors belonging to different receptor families can be functionally exchanged and confirm that a homodimer of G-CSFR can transduce the growth signal, whereas Fas must be oligomerized (probably trimerized) to transduce the apoptotic signal.

Animals↗
PubMed1998

Human pancreatic adenocarcinomas express Fas and Fas ligand yet are resistant to Fas-mediated apoptosis.

The Fas system, comprising the Fas receptor (Fas, CD95, APO-1) and its ligand, Fas ligand (FasL), is a central mediator of programmed cell death in various physiological and pathological processes. Recent evidence indicated that tumor cells can exploit this system to their benefit in the dialogue with the host immune system. We have shown that all human pancreatic adenocarcinoma cell lines tested by fluorescence-activated cell sorting analysis (6 of 6) and immunocytochemistry (12 of 12) were positive for Fas expression, as were normal and malignant duct cells in pancreatic tissue sections. However, despite Fas expression, pancreatic tumor cells have become largely resistant toward recombinant FasL- or anti-APO-1 agonistic antibody-induced apoptosis. This resistance correlated with high levels in pancreatic tumor cells of mRNA for FAP-1, a Fas-associated phosphatase that can block the apoptotic function of Fas. Using a variety of methodological approaches, we also present evidence for the production of FasL by pancreatic tumor cells because 6 of 6 pancreatic tumor cell lines were found to contain FasL mRNA as well as the Mr 40,000 and Mr 26,000 forms of the FasL protein. Likewise, pancreatic tissue revealed FasL-specific immunostaining in pancreatic tumor cells but not in the surrounding stroma. In coculture experiments, pancreatic tumor cells displayed a cytotoxic effect toward the Fas-sensitive Jurkat T-cell line, which could be inhibited by a FasL-specific neutralizing antibody. Together, these results support the recently proposed "counterattack model" for local deletion of tumor-reactive T-cells by tumor cell-derived FasL.

Adenocarcinoma↗