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The radio-sensitizing effect and tumor growth inhibition by cystine glutamate transporter (system xc-) inhibition in glioblastoma
DC Field | Value | Language |
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dc.contributor.author | 윤홍인 | - |
dc.date.accessioned | 2017-07-07T16:10:52Z | - |
dc.date.available | 2017-07-07T16:10:52Z | - |
dc.date.issued | 2016 | - |
dc.identifier.uri | https://ir.ymlib.yonsei.ac.kr/handle/22282913/148919 | - |
dc.description | 의과대학/박사 | - |
dc.description.abstract | Glioblastoma is the most aggressive brain tumor. Despite existing multimodal therapy, new therapeutic strategies are required. System xc-, composed of a light-chain subunit (xCT, SLC7A11) and a heavy chain subunit (CD98hc, SLC3A2), releases glutamate outside the cell and concurrently uptakes cystine in the cell at a 1 to 1 ratio. The increased intracellular cystine, due to uptake by system xc-, is transformed into glutathione (GSH) that is one of the most important antioxidants in cancer cells, contributing to cancer cell survival and proliferation. So, I investigated that the inhibition of system xc- could improve the radio-sensitivity and reduce the cell growth and migration in glioblastoma. Herein, I show that system xc- inhibition could enhance radio-sensitivity and repress glioblastoma progression and invasion. System xc- inhibition induces a decrease in intracellular GSH in glioblastoma. Irradiation combined with system xc- inhibition increases DNA double strand breaks (DSB) than that with irradiation alone in glioblastoma. The combination of irradiation and system xc- inhibition resulted in a significantly lower surviving fraction at each dose than irradiation alone. Irradiation could induce the change of mesenchymal markers. Additionally, the expression of the Cancer Genome Atlas (TCGA)-based markers of mesenchymal glioblastoma, CD44 and YKL-40, was elevated after the irradiation. System xc- inhibition reduced cell migration through the change of mesenchymal markers in glioblastoma. Although irradiation significantly increased cell movement, system xc- inhibition blocked the radiation-induced cell migration. System xc- inhibition is significantly related to decrease in mesenchymal markers, including SNAIL, vimentin, N-cadherin, alpha-SMA and FAP in glioblastoma. System xc- protein expression was significantly higher in the mesenchymal than that in the proneural human glioblastoma specimens. In conclusion, these findings demonstrate that system xc- inhibition in combination with irradiation could decrease cystine uptake and GSH, inducing an increase in DNA DSB. System xc- inhibition could enhance radio-sensitivity in glioblastoma. In addition, system xc- inhibition prevented the radiation-induced cell migration and affected mesenchymal features, which are adverse prognostic factors in glioblastoma. Taken together, my results indicate that the combination of radiation therapy (RT) and system xc- inhibition could improve therapeutic outcomes in glioblastoma. | - |
dc.description.statementOfResponsibility | open | - |
dc.publisher | Graduate School, Yonsei University | - |
dc.rights | CC BY-NC-ND 2.0 KR | - |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/2.0/kr/ | - |
dc.title | The radio-sensitizing effect and tumor growth inhibition by cystine glutamate transporter (system xc-) inhibition in glioblastoma | - |
dc.type | Thesis | - |
dc.contributor.department | Dept. of Radiation Oncology (방사선종양학교실) | - |
dc.contributor.localId | A04777 | - |
dc.contributor.alternativeName | Yoon, Hong In | - |
dc.contributor.affiliatedAuthor | 윤홍인 | - |
dc.type.local | Dissertation | - |
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