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)

Prion diseases are neurodegenerative disorders characterized by the accumulation of an abnormal isoform of the prion protein PrP(Sc). Human prion protein fragment, PrP (106-126) (prion protein peptide 106-126), may contain most of the pathological features associated with PrP(Sc). Hypoxic conditions elicit cellular responses adaptively designed to improve cell survival and have an important role in the process of cell survival. We investigate the effects of hypoxia on PrP (106-126)-induced apoptosis in the present study. Human neuroblastoma and glioblastoma cells were incubated with varied doses of PrP (106-126) under both normoxic or hypoxic conditions, in order to determine the regulatory effects of hypoxia on PrP (106-126)-induced apoptosis. The results indicate that hypoxia protects neuronal cells against PrP (106-126)-induced cell death by activating the Akt signal, which is inactivated by prion proteins, and inhibiting PrP (106-126)-induced caspase 3 activation. Low oxygen conditions increase the Bcl-2 protein, which is associated with anti-apoptotic signals, and recover the PrP (106-126)-induced reduction in mitochondrial transmembrane potential. This study demonstrates that hypoxia inhibits PrP (106-126)-induced neuron cell death by regulating Akt and Akt-related signaling, and it also suggests that prion-related neuronal damage and disease may be regulated by hypoxia or by hypoxic-inducing genes.
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PMID:Hypoxia protects neuronal cells from human prion protein fragment-induced apoptosis. 1991 74

MicroRNAs (miRNAs) are a class of endogenous small noncoding RNAs that regulate gene expression after transcription. Aberrant expression of miRNAs has been shown to be involved in tumorigenesis. We showed that miR-21 was one of the most frequently overexpressed miRNA in human glioblastoma (GBM) cell lines. To explore whether miR-21 can serve as a therapeutic target for glioblastoma, we downregulated miR-21 with a specific antisense oligonucleotide and found that apoptosis was induced and cell-cycle progression was inhibited in vitro in U251 (PTEN mutant) and LN229 (PTEN wild-type) GBM cells; xenograft tumors from antisense-treated U251 cells were suppressed in vivo. Antisense-miR-21-treated cells showed a decreased expression of EGFR, activated Akt, cyclin D, and Bcl-2. Although miR-21 is known to regulate PTEN and downregulation of miR-21 led to increased PTEN expression both endogenously and in a reporter gene assay, the GBM suppressor effect of antisense-miR-21 is most likely independent of PTEN regulation because U251 has mutant PTEN. Microarray analysis showed that the knockdown of miR-21 significantly altered expression of 169 genes involved in nine cell-cycle and signaling pathways. Taken together, our studies provide evidence that miR-21 may serve as a novel therapeutic target for malignant gliomas independent of PTEN status.
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PMID:Downregulation of miR-21 inhibits EGFR pathway and suppresses the growth of human glioblastoma cells independent of PTEN status. 2004 43

Constitutive activation of signal transducer and activator of transcription 3 (STAT3) signaling is frequently detected in cancer, promoting its emergence as a promising target for cancer treatment. Inhibiting constitutive STAT3 signaling represents a potential therapeutic approach. We used structure-based design to develop a nonpeptide, cell-permeable, small molecule, termed as LLL12, which targets STAT3. LLL12 was found to inhibit STAT3 phosphorylation (tyrosine 705) and induce apoptosis as indicated by the increases of cleaved caspase-3 and poly (ADP-ribose) polymerase in various breast, pancreatic, and glioblastoma cancer cell lines expressing elevated levels of STAT3 phosphorylation. LLL12 could also inhibit STAT3 phosphorylation induced by interleukin-6 in MDA-MB-453 breast cancer cells. The inhibition of STAT3 by LLL12 was confirmed by the inhibition of STAT3 DNA binding activity and STAT3-dependent transcriptional luciferase activity. Downstream targets of STAT3, cyclin D1, Bcl-2, and survivin were also downregulated by LLL12 at both protein and messenger RNA levels. LLL12 is a potent inhibitor of cell viability, with half-maximal inhibitory concentrations values ranging between 0.16 and 3.09 microM, which are lower than the reported JAK2 inhibitor WP1066 and STAT3 inhibitor S3I-201 in six cancer cell lines expressing elevated levels of STAT3 phosphorylation. In addition, LLL12 inhibits colony formation and cell migration and works synergistically with doxorubicin and gemcitabine. Furthermore, LLL12 demonstrated a potent inhibitory activity on breast and glioblastoma tumor growth in a mouse xenograft model. Our results indicate that LLL12 may be a potential therapeutic agent for human cancer cells expressing constitutive STAT3 signaling.
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PMID:A novel small molecule, LLL12, inhibits STAT3 phosphorylation and activities and exhibits potent growth-suppressive activity in human cancer cells. 2007 52

The exposure to benzene is a public health problem. Although the most well-known effect of benzene is hematopoietic toxicity, there is little information about the benzene and its metabolites effects on the central nervous system (CNS). This study examined the toxic effects of 1,2-dihydroxybenzene (catechol), a benzene metabolite, to human glioblastoma GL-15 cells. GL-15 cell cultures were used as a model to provide more information about the toxic effects of aromatic compounds to the CNS. Catechol induced time- and concentration-dependent cytotoxic effects. Morphological changes, such as the retraction of the cytoplasm and chromatin clumping, were seen in cells exposed to 200 microM catechol for 48 hours. In cells exposed to 600 microM catechol for 48 hours, 78.0% of them presented condensed nuclei, and the Comet assay showed DNA damage. The percentage of cells labeled with annexin V (apoptotic cells) was greater in the group exposed to catechol (20.7%) than in control cells (0.4%). Exposure to catechol at concentrations greater than 100 microM enhanced Bax levels, and a decrease in Bcl-2 level was observed after the exposure to 600 microM catechol for 48 hours. Furthermore, catechol depleted reduced glutathione. Hence, catechol induced cell death mainly by apoptosis.
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PMID:Catechol cytotoxicity in vitro: induction of glioblastoma cell death by apoptosis. 2009 27

EGFR and its constitutively activated variant EGFRvIII are linked to glioblastoma resistance to therapy, the mechanisms underlying this association, however, are still unclear. We report that in glioblastoma, EGFR/EGFRvIII paradoxically co-expresses with p53-upregulated modulator of apoptosis (PUMA), a proapoptotic member of the Bcl-2 family of proteins primarily located on the mitochondria. EGFR/EGFRvIII binds to PUMA constitutively and under apoptotic stress, and subsequently sequesters PUMA in the cytoplasm. The EGFR-PUMA interaction is independent of EGFR activation and is sustained under EGFR inhibition. A Bcl-2/Bcl-xL inhibitor that mimics PUMA activity sensitizes EGFR/EGFRvIII-expressing glioblastoma cells to Iressa. Collectively, we uncovered a novel kinase-independent function of EGFR/EGFRvIII that leads to tumor drug resistance.
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PMID:EGFR and EGFRvIII interact with PUMA to inhibit mitochondrial translocalization of PUMA and PUMA-mediated apoptosis independent of EGFR kinase activity. 2015 21

Radiotherapy is widely used in cancer treatment and biological studies. Multiple mechanisms induced by radiation, especially changes of the expression profile of genes, lead to the disruption of cellular homeostasis. MicroRNAs (miRNAs) are important post-transcriptional gene regulators and play an important role in response to cellular stress. Here we investigated the profiles of miRNA expression following exposure to radiation and the possible role of miRNAs in the modulation of radiosensitivity in the glioblastoma multiform U87MG cell line. MiRNA expression profiles revealed a limited set of miRNAs with altered expression in U87MG cells in response to radiation treatment. MiR-181a, a member of miR-181 family, was one of the down-regulated miRNAs, whose expression was further validated by qRT-PCR. The target mRNAs of radiation-responsive miRNAs were predicted with a target prediction tool. Transiently overexpressed miR-181a significantly sensitized malignant glioma cells to radiation treatment concurrent with the down-regulation of the protein Bcl-2 (B cell lymphoma/lewkmia-2). It indicates that miR-181a may modulate radiosensitivity by targeting Bcl-2 in human malignant glioma cells. These data suggest that radiation can affect miRNA expression, which regulates the cellular response, and miR-181a could be a target for enhancing the effect of radiation treatment on malignant glioma cells.
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PMID:MicroRNA-181a sensitizes human malignant glioma U87MG cells to radiation by targeting Bcl-2. 2020 84

We have previously shown that factors secreted by activated CTLs induce apoptosis in a panel of glioblastoma lines. In this study, we analyzed the expression of death receptors, activation of caspases and mRNA expression of 96 apoptotic genes in glioblastoma lines either sensitive or resistant to supernatant of activated CTLs. Our results indicate that exposure to supernatant triggers several pathways of caspase activation in glioblastoma lines involved in the initiation of both extrinsic and intrinsic apoptosis. High steady-state levels of Bcl-2 were identified as potentially accounting for the resistance of a proportion of glioblastoma lines to factors secreted by activated CTLs.
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PMID:Cytotoxic T-lymphocytes secrete soluble factors that induce caspase-mediated apoptosis in glioblastoma cell lines. 2048 78

Glioblastoma is a highly lethal brain tumor of the human primary nervous system tumors. Previous studies demonstrated that glioblastoma stem cells were able to initiate and reform the original cancer. In this study, we found that there were expression and activation of STAT3, a key signal transduction factor and oncoprotein, in human glioblastoma stem cells (GSCs). STAT3 plays a key role in proliferation, apoptosis and differentiation in embryonic stem cells and several cancer types. To investigate the effects of STAT3 on human GSCs, the expression and activation of STAT3 were suppressed by RNAi mediated with lentivirus. We demonstrated that siRNA of STAT3 significantly suppressed STAT3 expression and activation and resulted in inhibition of cell growth in GSCs. Knockdown of STAT3 induces apoptosis and reduces significantly expression of Bcl-2 and cyclin-D in human primary GSCs, whereas no significance was achieved in BAX and caspase-3 expression. Inhibition of STAT3 expression is associated not only with decreasing of CD133+ cell proportion and increasing of GFAP and MBP expression, but also with decrease of the capacity to initiate a tumor in human primary GSCs. Together, these studies suggest that STAT3 is an important target for human GSCs in regulation of GSCs growth, apoptosis, differentiation and tumorigenic potential.
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PMID:Knockdown of STAT3 expression by RNAi suppresses growth and induces apoptosis and differentiation in glioblastoma stem cells. 2051 2

Curcumin has been verified as an anti-cancer compound via multiple molecular targets. Its effective mechanisms include cell cycle arrest, inducing apoptosis, suppressing oncogenes, and enhancing tumor suppressor genes. The resistance of cells to chemotherapy, however, derives from the variable genetic aberration of cancer cells. Consequently, the core signaling pathways of glioblastoma have been explored to evaluate the efficacy of curcumin in proceeding through mutated genes in those pathways. In this study, the efficacy of curcumin was investigated in DBTRG cells. The cytotoxic ability was detected with MTT assay, and the influence of the cell cycle was checked with flow cytometry. The influence of the core signaling pathways was evaluated by Western blotting through the predominantly mutated proteins which included p53, p21, and cdc2 in the p53 pathway, CDKN2A/p16 and RB in the RB pathway, and EGFR, mTOR, Ras, PTEN, and Akt in the RTK-Ras-PI3K pathway. In addition, the apoptotic effect was determined by apoptosis-associated proteins Bcl-2, Bax, and caspase 3. Curcumin exhibits superior cytotoxicity on glioblastoma in a dose- and time-dependent manner in the MTT assay. In the core signaling pathways of glioblastoma, curcumin either significantly influences the p53 pathway by enhancing p53 and p21 and suppressing cdc2 or significantly inhibits the RB pathway by enhancing CDKN2A/p16 and suppressing phosphorylated RB. In the apoptotic pathway, the Bax and caspase 3 are significantly suppressed by curcumin and the Giemsa stain elucidates apoptotic features of DBTRG cells as well. In conclusion, curcumin appears to be an effective anti-glioblastoma drug through inhibition of the two core signaling pathways and promotion of the apoptotic pathway.
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PMID:The anti-cancer efficacy of curcumin scrutinized through core signaling pathways in glioblastoma. 2059 1

MicroRNAs (miRNAs) are small noncoding RNA molecules that regulate protein expression by cleaving or repressing the translation of target mRNAs. In mammal animals, their function mainly represses the target mRNAs transcripts via imperfectly complementary to the 3'UTR of target mRNAs. Several miRNAs have been recently reported to be involved in modulation of glioma development, especially some up-regulated miRNAs, such as microRNA-21 (miR-21), which has been found to function as an oncogene in cultured glioblastoma multiforme cells. Temozolomide (TMZ), an alkylating agent, is a promising chemotherapeutic agent for treating glioblastoma. However, resistance develops quickly and with high frequency. To explore the mechanism of resistance, we found that miR-21 could protect human glioblastoma U87MG cells from TMZ induced apoptosis. Our studies showed that TMZ markedly enhanced apoptosis in U87MG cells compared with untreated cells (P<0.05). However, over-express miR-21 in U87MG cells could significantly reduce TMZ-induced apoptosis (P<0.05). Pro-apoptotic Bax and anti-apoptotic Bcl-2 proteins are known to regulate the apoptosis of glioma cells. Bcl-2, resistance to induction of apoptosis, constitutes one major obstacle to chemotherapy in many cancer cells. Bax is shown to correlate with an increased survival of glioblastoma multiforme patients. Further research demonstrated that the mechanism was associated with a shift in Bax/Bcl-2 ratio and change in caspase-3 activity. Compared to control cells, cells treated with TMZ showed a significant increase in the Bax/Bcl-2 ratio and caspase-3 activity (P<0.01). However, such effect was partly prevented by treatment of cells with miR-21 overexpression before, which appeared to downregulate the Bax expression, upregulate the Bcl-2 expression and decrease caspase-3 activity. Taken together, these results suggested that over-express miR-21 could inhibit TMZ-induced apoptosis in U87MG cells, at least in part, by decreasing Bax/Bcl-2 ratio and caspase-3 activity, which highlighted the possibility of miR-21 overexpression in the clinical resistance to chemotherapeutic therapy of TMZ.
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PMID:MiR-21 protected human glioblastoma U87MG cells from chemotherapeutic drug temozolomide induced apoptosis by decreasing Bax/Bcl-2 ratio and caspase-3 activity. 2063 39


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