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  • Marie, Suely K.  (3)
  • Soares, Roseli S.  (3)
  • English  (3)
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  • English  (3)
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  • 1
    Online Resource
    Online Resource
    Abstract 3739: Understanding the link between glutamine metabolism and angiogenesis in astrocytoma
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 3739-3739
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 3739-3739
    Abstract: Angiogenic switch is a hallmark for tumor growth, and strategies to inhibit this process have been pursued for cancer therapy, but with limited long-term efficacy. Recently, targeting endothelial cell (EC) metabolism emerged as an alternative to regulate angiogenesis. In fact, glutamine metabolism is essential for EC sprouting in vitro, and the consumption/secretion rate measurements revealed that proliferating ECs consumed glutamine more than any other amino acid. Glutamine is transported into the cells and converted into α-ketoglutarate to enter the tricarboxylic acid cycle through glutaminolysis, which is upregulated in cancer. Glutaminase (coded by GLS), the main regulator of this pathway, presents two isoforms: GLSiso1 and GLSiso2. We have analyzed the expression level of both GLS isoforms in different grades of astrocytoma, with a gradual increase of their expressions in parallel to the malignancy. GLSiso1 was highly expressed in normal brain samples, in contrast to low GLSiso2 expression, indicating GLSiso2 as a more eligible therapeutic target. GLSiso2-specific transcript inhibition by siRNA in GBM U87MG cells lead to significant decrease of tumor cell proliferation, and a temozolomide-sensitizing effect, relative to NTC-controls. The RNASeq transcriptome analysis of these GLSiso2-silenced cells revealed a differential expression of genes related to blood vessel development, extracellular matrix organization, angiogenesis and tube development with FDR of 4.95e-04, 5.25e-06, 5.92e-05, 8.6e-06 and 1.0e-04, respectively. The immunohistochemistry analysis in human astrocytoma FFPE samples demonstrated GLS positivity on tumor cells and blood vessels, with higher protein expression in more malignant astrocytoma. Such observation corroborated the transcriptomic finding of GLSiso2 participation in the EC compartment. Moreover, the system biology analysis revealed an interesting net among GLS, TP53, ITB1, TGFBI, TGFBR1/2, COL1A1/2, COL5A2, LUM, ENG, ANGPT1 connecting genes related to metabolism, extracellular matrix and angiogenesis. In the search for the most suitable EC line to study the impact of GLS isoforms on the vessel compartment, we observed that HUVEC immortalized umbilical EC line presented higher expression of GLSiso2 than GLSiso1. Chemical blockade of the total GLS by BPTES and 968 was tested in HUVEC cells and a significant proliferation and migration decrease were observed. Further GLSiso2 specific silencing of ECs might clarify the crosstalk between tumor cells and ECs, and will allow the identification of key targets in their metabolic reprogramming during tumor growth. Citation Format: Yollanda E. Franco, Roseli S. Soares, Marina T. Lima, Antonio M. Lerario, Sueli M. Shinjo, Suely K. Marie. Understanding the link between glutamine metabolism and angiogenesis in astrocytoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3739.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-3739
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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    Location Call Number Limitation Availability
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  • 2
    Online Resource
    Online Resource
    Abstract 899: CD99 plays an important role in glioblastoma cell migration
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 899-899
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 899-899
    Abstract: Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults and the standard treatment consists of surgical resection of the tumor followed by radiation and chemotherapy with temozolomide. A combination of standard therapy with other biologically-based therapies is necessary to improve the survival of patients with GBM, which currently stands only to 15-17 months. In this sense many studies have been developed in pursuit of expressed membrane proteins in GBM, which are potential targets for immunotherapy. Our laboratory demonstrated increased CD99 mRNA and protein expression in GBM samples. CD99 has a key role in several biological processes, including cell adhesion, migration, apoptosis, differentiation of T cells and thymocytes, diapedesis of lymphocytes to inflamed vascular endothelium, maintenance of cellular morphology and regulation of intracellular membrane protein trafficking. In this study, the transcriptome of two GBM cell lines (U87MG and A172) transfected with siRNA for CD99 were analyzed in relation to the non-target control (NTC). A total of 728 genes (hypoexpressed with fold change ≤-1.5 relative to NTC or hyperexpressed with fold change ≥1.5 relative to NTC) were observed in both cell lines. An enrichment analysis by MetaCoreTM revealed the following processes as the most significant: (1) Cytoskeleton_Regulation of cytoskeleton rearrangement, (2) Cell adhesion_Cell-matrix interactions (3) Development_Blood vessel morphogenesis. Further, both cell lines were silenced for CD99 expression by shRNA (two clones) to perform functional assays, as wound healing (migration assay), adhesion, invasion and apoptosis. The CD99 knockdown reduced migration in both cell lines, with the highest decrease of the migration observed in the highest CD99 knockdown. Adhesion assay was performed using fibronectin as an extracellular matrix substrate. U87MG cells showed greater adhesion to fibronectin than the control (scrambled shRNA). On the other hand, A172 cells knocked down for CD99 presented lower adherence to fibronectin than the control. Apoptosis analysis with shCD99 U87MG cells showed a tendency of cells entering into late apoptosis when treated with temozolamide for 48 hours, but the same was not observed in shCD99 A172 cells. Additionally, CD99 (RPE) and phaloidin (Alexa Fluor 488) colocalized at lamellipodia, suggesting that CD99 is related to cytoskeleton rearrangement in both GBM cell lines. The different phenotypic behavior of migration and apoptosis observed in these two GBM cell lines with different somatic mutation background may be due to distinct signaling activation. Migration/invasion is the major characteristics of GBM which limits the surgical tumor resection, and consequently leads to tumor recurrence. Therefore, further analysis of CD99 activating pathways in the context of cell migration is worthwhile to unveil new therapeutic strategies to halt GBM progression. Citation Format: Lais C. Cardoso, Antonio M. Lerario, Suely K. Marie, Roseli S. Soares, Sueli M. Oba-Shinjo. CD99 plays an important role in glioblastoma cell migration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 899. doi:10.1158/1538-7445.AM2017-899
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-899
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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  • 3
    Online Resource
    Online Resource
    Abstract 2605: LOXL3 knock out affects pathways which involve cytoskeleton regulation, proliferation and apoptosis in glioblastoma cells
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 2605-2605
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 2605-2605
    Abstract: Lysyl oxidase-like 3 (LOXL3), belonging to the lysyl oxidase family of copper-dependent amino oxidase, is responsible for the crosslinking of collagen and elastin. In tumors, the presence of LOXL3 has been associated with genomic stability, cell proliferation, and metastasis. In silico analysis has shown that glioblastoma was among the tumors with the highest LOXL3 expression levels. Moreover, LOXL3 expression increased with malignancy grade amongst diffusely infiltrative astrocytomas (from grade 2 to 4). In the present work, CRISPR-Cas9 gene editing was used to knock out LOXL3 in the human glioma U87MG cell line to evaluate the role of LOXL3 in glioblastoma. Analyses of protein expression level and genomic mutation mediated by CRISPR-Cas9 by two different sgRNA (denominated sgRNA1 and 2) were performed and the knock out efficiency and genome editing were confirmed. Transcriptome analysis of these cells revealed a downregulation of genes that coded for proteins involved in microtubule organization, cell division, and vesicle trafficking. On the other hand, upregulated genes when LOXL3 was knocked out in U87MG cells were involved in actin cytoskeleton, negative regulation of gene transcription, including chromatin remodeling, and cell-cell adhesion. Functional in vitro assays showed that LOXL3 knocked out cells presented decreased cell proliferation due to longer cell cycles with increased G1 and G2/M checkpoints compared to control cells. Additionally, LOXL3 knocked out U87MG cells presented a higher percentage of cells in the early phase of apoptosis with an increment after temozolomide treatment. Our results suggest an important role of LOXL3 in glioblastoma possibly mediated by cytoskeleton regulation, affecting cell proliferation, cell cycle, and cell death. These results reinforced the importance of LOXL3 in tumors, especially in glioblastoma, highlighting it as a potential therapeutic target. Citation Format: Talita S. Laurentino, Roseli S. Soares, Antonio M. Lerario, Suely K. Marie, Sueli Mieko Oba-Shinjo. LOXL3 knock out affects pathways which involve cytoskeleton regulation, proliferation and apoptosis in glioblastoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2605.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-2605
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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