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  • Dasari, Venkata Ramesh  (3)
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  • 1
    Online Resource
    Online Resource
    Abstract 434: Radiation-induced matrix metalloprotease-9 promotes mesenchymal transition of Daoy cells and initiates activation of pro-matrix metalloprotease-2.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 434-434
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 434-434
    Abstract: Ionizing radiation is an efficient therapeutic modality against cancer and a potent carcinogenic agent with the ability to alter cellular genotype. Earlier, we reported that medulloblastoma cells exposed to ionizing radiation showed enhanced invasive and adhesive characteristics. Invasion is the cumulative effort of cells to degrade the extracellular matrix (ECM) and to modulate cellular phenotype to invade the ECM. Therefore, we examined the modulation gained by irradiated medulloblastoma cells leading to enhanced invasiveness. Radiation-induced invasion increased with the increase in the recovery time after radiation treatment and was identified to be associated with MMP-9/MMP-2 activity. Radiation enhanced the expression of MMP-9 and induced the cleavage of pro-MMP-2 into active form, and the latter was associated with MT-MMP-1 expression. A significant time lag observed between the radiation exposure time and MMP-2 activation was identified as a period required for the irradiated cells to acquire cellular alteration, such as mesenchymal characteristics. Recombinant protein(s) and inhibitor(s) studies demonstrated that radiation-induced MT-MMP-1 expression and MMP-2 activation are in harmony with JNK activation. MMP-9 gene silencing and protein supplementation studies confirmed that MMP-9 activates JNK signaling and potent inducers of mesenchymal markers such as Snai1 and N-Cadherin. Further, gene-specific silencing of either MMP-9 or N-Cadherin showed significant reduction of MMP-2 activation in irradiated Daoy cells. Collectively, our results provide an insight on the role of MMP-9 in radiation-induced invasion and in initiating signaling cascades that modulate Daoy cells to acquire mesenchymal characteristics and activate MMP-2. Citation Format: Arun Kumar Nalla, Swapna Asuthkar, Venkata Ramesh Dasari, Jasti S. Rao. Radiation-induced matrix metalloprotease-9 promotes mesenchymal transition of Daoy cells and initiates activation of pro-matrix metalloprotease-2. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 434. doi:10.1158/1538-7445.AM2013-434
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-434
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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    Online Resource
  • 2
    Online Resource
    Online Resource
    Abstract 1731: Decreased cyclin B1 expression contributes to mitochondrial apoptosis in medulloblastoma.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 1731-1731
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 1731-1731
    Abstract: Medulloblastoma, the most common malignant pediatric brain tumor, remains difficult to cure. Previously, we have shown that downregulation of MMP-9 and uPAR induces Chk1-mediated G2/M cell-cycle arrest in medulloblastoma cells. In this study, we observed that downregulation of MMP-9 in nude mice D283 xenografts downregulated the expression of cyclin B1. Increasing evidence indicates that the deregulation of cyclin B1 is involved in neoplastic transformation, suggesting that inhibition of cyclin B1 could be an attractive strategy for anti-tumor therapy. To determine the effect of downregulation of cyclin B1, we treated medulloblastoma cells with nocodazole, which is an anti-neoplastic agent. Nocodazole-treated cells have undergone G2/M cell-cycle arrest because of the mitotic spindle arrest. Prolonged arrest of cells in mitosis due to nocodazole treatment typically results in cell death by apoptosis. Hence, we confirmed the induction of apoptosis in medulloblastoma cells by TUNEL analysis. Immunoblot analysis of cell cycle checkpoint proteins Chk1, Chk2 and cyclin B1 revealed that they were downregulated in combination treatments of shMMP-9 with radiation. Further, apoptotic proteins BAD, BAX and BAK were highly upregulated, which shows the involvement of mitochondria-mediated apoptosis in our treatments. In vivo analysis of BAD molecules in D283 nude mice xenografts confirmed that downregulation of cyclin B1 induces BAD-mediated apoptotic death in medulloblastoma tumors treated with either shMMP-9 alone or in combination with radiation. With this study, we demonstrate that downregulation of cyclin B1 is an effective and specific approach to induce apoptosis for effective anti-tumor therapy against medulloblastoma. Citation Format: Venkata Ramesh Dasari, Swapna Asuthkar, Arun Kumar Nalla, Jasti S. Rao. Decreased cyclin B1 expression contributes to mitochondrial apoptosis in medulloblastoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1731. doi:10.1158/1538-7445.AM2013-1731
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-1731
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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    Online Resource
  • 3
    Online Resource
    Online Resource
    Abstract 3904: uPAR-regulated nuclear translocation of hand-1 mediates vascular radiosensitivity in medulloblastoma tumors.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 3904-3904
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 3904-3904
    Abstract: Urokinase-type plasminogen activator (uPAR) is overexpressed in the tumor-stromal invasive microenvironment in many human cancers including medulloblastoma. The role of uPAR in tumor progression and angiogenesis has been well characterized. Most recently, in medulloblastoma cells, we showed that ionizing radiation (IR)-induced uPAR is a potent activator of cancer stem cell (CSC)-like properties and is associated with various transcription factors that are involved during embryonic development and cancer. In this study, we show that the uPAR protein is a cytoplasmic sequestration factor for a novel basic helix-loop-helix (bHLH) transcription factor, Hand-1. The Hand-1 protein plays an essential role in differentiation of trophoblast giant cells and cardiac morphogenesis, and yet its precise cellular function and its contributions to cancer remain mostly unknown. In the present study, we observed that Hand-1 protein is upregulated in uPAR shRNA-treated medulloblastoma cells and accompanies sustained cell growth and angiogenesis. Furthermore, IR-induced uPAR overexpression negatively regulates Hand-1 activity and results in the stabilization of angiogenesis promoting molecules, such as HIF-1 alpha. Finally, uPAR overexpression and its association with Hand-1 after IR treatment indicate that uPAR is capable of regulating Hand-1 and that uPAR has a role in the process of IR-induced tumor angiogenesis. Citation Format: Swapna Asuthkar, Kiran Kumar Velpula, Arun Kumar Nalla, Venkateswara Rao Gogineni, Venkata Ramesh Dasari, Bharathi Gorantla, Jasti S. Rao. uPAR-regulated nuclear translocation of hand-1 mediates vascular radiosensitivity in medulloblastoma tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3904. doi:10.1158/1538-7445.AM2013-3904
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-3904
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
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