Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fas (APO-1/CD95) ligand (FasL) and its receptor, Fas, play a key role in the regulation of apoptosis in the immune system. FasL acts as a cytotoxic effector molecule to Fas-expressing malignant tumor cells; however, it has recently been suggested that FasL also acts as a possible mediator of tumor immune privilege. We studied FasL expression in glioblastoma cell lines and a series of human glioma specimens by Western blotting and immunohistochemistry. In addition, quantitative analysis of T-cell infiltration in these tumors was performed. FasL expression was seen in all cell lines and in 9 of 14 specimens by Western blotting and immunohistochemistry. The distribution of FasL was recognized in the cytoplasm of tumor cells (5 of 9) and in the vascular endothelium (4 of 9). Both types of FasL expression were associated with a significant reduction (p < 0.05) in T-cell infiltration when compared with FasL-negative areas within the same tumor or FasL-negative specimens. Since T-cell apoptosis could be induced by FasL-expressing tumor cells, the present findings suggest that apoptosis induction by FasL expressed on tumor cells and/or vascular endothelium might be one mechanism for T-cell depletion in astrocytic tumor tissues.
 ...
PMID:Fas ligand expression and depletion of T-cell infiltration in astrocytic tumors. 1151 72

The mitochondrial peripheral benzodiazepine receptor (mPBR) is involved in a functional structure designated as the permeability transition pore, which controls apoptosis. Binding of Fas/APO-1/CD95 triggers a prototypic apoptosis-inducing pathway. Using four different human tumor cell lines (T-cell Jurkat, neuroblastoma SHEP, osteosarcoma 143N2, and glioblastoma SNB79 cell lines), all of which express CD95 and mPBR, we investigated the potential role of mPBR ligands in CD95-induced apoptosis. We show that, in vitro, the three mPBR ligands tested (RO5-4864, PK11195, and diazepam) enhanced apoptosis induced by anti-CD95 antibody in Jurkat cells, as demonstrated by mitochondrial transmembrane potential drop and DNA fragmentation. In contrast, RO5-4864, but not PK11195 or diazepam, enhanced anti-CD95 apoptosis in all other cell lines. These effects were obtained in Bcl-2-overexpressing SHEP cell lines, but not in Bcl-X(L) SHEP cell lines. Enhancement of anti-CD95 antibody-induced apoptosis by RO5-4864 was characterized by an increased mitochondrial release of cytochrome c and Smac/DIABLO proteins and an enhanced activation of caspases 9 and 3, suggesting a mitochondrion-dependent mechanism. Preincubation of cells with the different mPBR ligands or anti-CD95 did not affect the levels of expression of either mPBR or CD95. In vivo, we found that the RO5-4864 mPBR ligand significantly increased the growth inhibition induced by two chemotherapeutic agents, etoposide and ifosfamide, using two human small cell lung cancers xenografted into nude mice. Peripheral benzodiazepine receptor ligands may therefore act as chemosensitizing agents for the treatment of human neoplasms.
 ...
PMID:Peripheral benzodiazepine receptor ligands reverse apoptosis resistance of cancer cells in vitro and in vivo. 1188 10

The expression of the death receptor Fas/CD95 is cell type-specific and can be modulated by different cytotoxic treatments. In spite of a frequent expression of Fas/CD95 in high-grade gliomas, these tumours are typically refractory to conventional therapy. Using a human glioblastoma cell line (GBM), we explored the possibility of modulating susceptibility to Fas/CD95-mediated apoptosis following cytotoxic treatment. GBM cells were sensitive to the antiproliferative effects of topoisomerase I inhibitors (topotecan and a novel lipophilic analog CPT83) and taxol, less sensitive to cisplatin and, in any case, rather resistant to drug-induced apoptosis. This pattern of cellular response was consistent with p53 mutation. GBM cells expressed low levels of Fas/CD95, which was associated with low susceptibility to antibody-stimulated Fas/CD95-mediated apoptosis. A significant up-regulation of Fas/CD95 expression was detected after exposure to topotecan and CPT83, whereas cisplatin induced a low increase and taxol did not modify Fas/CD95 expression. In addition, after treatment with topoisomerase I inhibitors, the up-regulation of Fas/CD95 resulted in an increased susceptibility of GBM cells to antibody-stimulated Fas/CD95-mediated apoptosis, while no synergistic effects were detected after treatment with cisplatin or taxol. Our data suggest that Fas/CD95 up-regulation can be a common response to DNA damage, whereas sensitisation to Fas/CD95-mediated apoptosis appears to be dependent on the type of DNA damage and on the pathway of cellular response. The observed effects might have important therapeutic implications for the design of novel therapeutic strategies in the treatment of malignant gliomas.
 ...
PMID:Fas/CD95-mediated apoptosis in human glioblastoma cells: a target for sensitisation to topoisomerase I inhibitors. 1191 40

Ceramide is a physiologic regulator of growth and differentiation in mammalian cells. In this study, the relationship between ceramide and FLICE inhibitory protein (FLIP) in the induction of apoptosis in glioblastoma cell lines was investigated. We found that LN215 cells were slightly more sensitive to Fas-mediated apoptosis than LN319 cells, which were more sensitive to ceramide than LN215 cells. FLIP was expressed in LN319 and LN215 cells constitutively, and this expression decreased with treatment of ceramide in LN215 cells, which might cause LN215 cells to be more sensitive to Fas-mediated apoptosis at lower level stimulation. In LN319 cells FLIP levels were not modified by ceramide treatment and the level of cell death induced by anti-Fas antibody was not affected. Our results suggest that FLIP may be down-regulated by low levels of ceramide in LN215 cells, which causes LN215 cells to be more sensitive to Fas-mediated apoptosis, whereas LN319 cells remain resistant.
 ...
PMID:Ceramide increases Fas-mediated apoptosis in glioblastoma cells through FLIP down-regulation. 1263 60

Several studies have recently demonstrated that human gliomas express Fas, Fas ligand (FasL), Bcl-2 and TGFbeta2 at some degree. These factors are considered to interact with apoptotic processes and to have immuno-reactive potential. Their role for tumor evasion from the immune surveillance is currently under examination. To date, there is only limited information about the definite expression patterns of these four factors in human gliomas, particularly in pilocytic astrocytoma (PA) and recurrent tumors. We analyzed 75 human gliomas for the immunohistochemical expression of Fas, FasL, Bcl-2, and TGFbeta2: (1) 25 PAs (WHO grade I), (2) 25 primary glioblastomas (WHO grade IV), and (3) 25 paired initial and recurrent glioblastomas (WHO grade IV), respectively. Co-expression of all four factors was present in the majority of specimens, i.e. in 72% (18/25) of PAs and 88% (47/50) of primary glioblastomas. Pilocytic astrocytomas showed significantly higher scores of TGFbeta2 expression (p < 0.05) and significantly lower Fas, Fas ligand and Bcl-2 scores (p < 0.05) than glioblastomas. There were no significant expression differences in initial versus recurrent glioblastoma specimens. Likewise, no significant correlation was observed between protein expression and clinical parameters, i.e. total survival time or progression free survival time, as documented by Kaplan-Meier method and log rank-test. In conclusion, Fas, FasL, Bcl-2 and TGFbeta2 are differently expressed in PAs versus glioblastomas. These factors, however, are not associated with patient prognosis. The broad co-expression of these factors may enable new therapeutic approaches in the future.
 ...
PMID:Protein expression of Fas, Fas ligand, Bcl-2 and TGFbeta2 and correlation with survival in initial and recurrent human gliomas. 1507 45

DNA-dependent protein kinase (DNA-PK), a nuclear serine/threonine kinase, is responsible for the DNA double-strand break repair. Cells lacking or with dysfunctional DNA-PK are often associated with mis-repair, chromosome aberrations, and complex exchanges, all of which are known to contribute to the development of human cancers including glioblastoma. Two human glioblastoma cell lines were used in the experiment, M059J cells lacking the catalytic subunit of DNA-PK, and their isogenic but DNA-PK proficient counterpart, M059K. We found that M059K cells were much more sensitive to staurosporine (STS) treatment than M059J cells, as demonstrated by MTT assay, TUNEL detection, and annexin-V and propidium iodide (PI) staining. A possible mechanism responsible for the different sensitivity in these two cell lines was explored by the examination of Bcl-2, Bax, Bak, and Fas. The cell death stimulus increased anti-apoptotic Bcl-2 and decreased pro-apoptotic Bcl-2 members (Bak and Bax) and Fas in glioblastoma cells deficient in DNA-PK. Activation of DNA-PK is known to promote cell death of human tumor cells via modulation of p53, which can down-regulate the anti-apoptotic Bcl-2 member proteins, induce pro-apoptotic Bcl-2 family members and promote a Bax-Bak interaction. Our experiment also demonstrated that the mode of glioblastoma cell death induced by STS consisted of both apoptosis and necrosis and the percentage of cell death in both modes was similar in glioblastoma cell lines either lacking DNA-PK or containing intact DNA-PK. Taken together, our findings suggest that DNA-PK has a positive role in the regulation of apoptosis in human glioblastomas. The aberrant expression of Bcl-2 family members and Fas was, at least in part, responsible for decreased sensitivity of DNA-PK deficient glioblastoma cells to cell death stimuli.
 ...
PMID:Glioblastoma cells deficient in DNA-dependent protein kinase are resistant to cell death. 1549 13

Norcantharidin (NCTD), the demethylated analogue of cantharidin, has been used to treat human cancers in China since 1984. It was recently found to be capable of inducing apoptosis in human colon carcinoma, hepatoma and glioblastoma cells by way of an elusive mechanism. In this study, we demonstrated that NCTD also induces apoptosis in human oral cancer cell lines SAS (p53 wild-type phenotype) and Ca9-22 (p53 mutant) as evidenced by nuclear condensation, TUNEL labeling, DNA fragmentation and cleavage of PARP. Apoptosis induced by NCTD was both dose- and time-dependent. We found NCTD did not induce Fas and FasL, implying that it activated other apoptosis pathways. Our data showed that NCTD caused accumulation of cytosolic cytochrome c and activation of caspase-9, suggesting that apoptosis occurred via the mitochondria mediated pathway. NCTD enhanced the expression of Bax in SAS cells consistent with their p53 status. Moreover, we showed that NCTD downregulated the expression of Bcl-2 in Ca9-22 and Bcl-XL in SAS. Our results suggest that NCTD-induced apoptosis in oral cancer cells may be mediated by an increase in the ratios of proapoptotic to antiapoptotic proteins. Since oral cancer cells with mutant p53 or elevated Bcl-XL levels showed resistance to multiple chemotherapeutic agents, NCTD may overcome the chemoresistance of these cells and provide potential new avenues for treatment.
 ...
PMID:Norcantharidin-induced apoptosis in oral cancer cells is associated with an increase of proapoptotic to antiapoptotic protein ratio. 1559 95

Necrosis in glioblastoma is often associated with high levels of Fas (APO-1), HIF-1alpha and PARP expression. The presence of such molecules suggests a regulative element to cell death within this tissue, which may involve p53. We aimed to establish whether p53 and its downstream targets Bax, MDM2 and p21 play a role in perinecrotic cell death in glioblastoma. Following sequencing of the p53 gene in U87 and U373 glioma cell lines, p53 was found to be reactive in the p53 wild-type line U87 in response to hypoxia but not in the p53 mutant line, U373. Although no increase in perinecrotic p53 expression was detected in spheroid cultures derived from these lines, a 60 kDa MDM2 isoform lacking a C-terminal domain showed perinecrotic localization, irrespective of p53 status. Similar findings were observed surrounding regions of necrosis in 80% of glioblastoma biopsies examined. Increasing levels of wild-type p53 did not affect cell death in U87 spheroid cultures but killed all U373 cells 3 days post transfection. Dominant negative p53 did not affect cell death in U373 and U87 spheroid cultures. Although p53 accumulation appeared not to be important for the onset of cell death both in spheroid and biopsy cases, high levels of perinecrotic 60 kDa MDM2 may have implications for glioma cell death susceptibility in both p53 mutant and wild-type tumour cell populations.
 ...
PMID:Discovery of a perinecrotic 60 kDa MDM2 isoform within glioma spheroids and glioblastoma biopsy material. 1577 12

Interleukin-8 (IL-8, or CXCL8), which is a chemokine with a defining CXC amino acid motif that was initially characterized for its leukocyte chemotactic activity, is now known to possess tumorigenic and proangiogenic properties as well. In human gliomas, IL-8 is expressed and secreted at high levels both in vitro and in vivo, and recent experiments suggest it is critical to glial tumor neovascularity and progression. Levels of IL-8 correlate with histologic grade in glial neoplasms, and the most malignant form, glioblastoma, shows the highest expression in pseudopalisading cells around necrosis, suggesting that hypoxia/anoxia may stimulate expression. In addition to hypoxia/anoxia stimulation, increased IL-8 in gliomas occurs in response to Fas ligation, death receptor activation, cytosolic Ca(2+), TNF-alpha, IL-1, and other cytokines and various cellular stresses. The IL-8 promoter contains binding sites for the transcription factors NF-kappaB, AP-1, and C-EBP/NF-IL-6, among others. AP-1 has been shown to mediate IL-8 upregulation by anoxia in gliomas. The potential tumor suppressor ING4 was recently shown to be a critical regulator of NF-kappaB-mediated IL-8 transcription and subsequent angiogenesis in gliomas. The IL-8 receptors that could contribute to IL-8-mediated tumorigenic and angiogenic responses include CXCR1 and CXCR2, both of which are G-protein coupled, and the Duffy antigen receptor for cytokines, which has no defined intracellular signaling capabilities. The proangiogenic activity of IL-8 occurs predominantly following binding to CXCR2, but CXCR1 appears to contribute as well through independent, small-GTPase activity. A precise definition of the mechanisms by which IL-8 exerts its proangiogenic functions requires further study for the development of effective IL-8-targeted therapies.
 ...
PMID:The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis. 1583 Dec 31

Cancer cells are known to express cell surface molecules such as specific antigens or cytokine receptors, e.g., EGFR, Fas/CD95, gp100, HER-2/neu, IL-13Ralpha2, and MAGE. Among them, interleukin-13 receptor (IL-13R) alpha2 chain is expressed on certain types of cancer cells including glioblastoma, AIDS Kaposi's sarcoma, and head and neck cancer. This protein is one of the receptor components for IL-13, a Th2 cell-derived pleiotropic immune regulatory cytokine. IL-13Ralpha2 chain on these cancer cells can be targeted with a receptor-directed cytotoxin termed IL13-PE to induce specific cancer cell killing, however, this molecule does not mediate cytotoxicity to cells that do not express or express low levels of IL-13Ralpha2. In order to achieve a broad therapeutic window for IL13-PE, plasmid-mediated gene transfer of IL-13Ralpha2 in cancer cells was employed in vitro and in vivo. Cancer cells transfected with IL-13Ralpha2 demonstrated increased binding to IL-13 and sensitivity to IL13-PE in vitro. In vivo intratumoral gene transfer of IL-13Ralpha2 profoundly enhanced the antitumor activity of IL13-PE, providing complete elimination of established tumor in some xenografts. In this review article, current findings from IL-13Ralpha2 gene transfer in a variety of human cancer models in nude mice are summarized. In addition, safety issues and possible future directions utilizing this therapeutic approach are discussed.
 ...
PMID:Cancer gene therapy utilizing interleukin-13 receptor alpha2 chain. 1585 29


<< Previous 1 2 3 4 5 6 7 Next >>