期刊
MOLECULAR MEDICINE REPORTS
卷 11, 期 6, 页码 4165-4173出版社
SPANDIDOS PUBL LTD
DOI: 10.3892/mmr.2015.3255
关键词
p53 up-regulated modulator of apoptosis; glioblastoma; temozolomide; drug resistance; apoptosis; O-6-methylguanine-DNA-methyltransferase
资金
- National Natural Science Foundation of China [81201991, 81470115]
- Science and Technology Research Program of Shanxi Province [20110313011-3]
- Basic Research Program of Shanxi Province [2012021035-4]
- Doctoral Foundation of the First Hospital of Shanxi Medical University [YB1109]
Malignant glioma is a highly aggressive brain tumor with a poor prognosis. Chemotherapy has been observed to prolong overall survival rate and temozolomide (TMZ), a promising chemotherapeutic agent for treating glioblastoma (GBM), possesses the most effective clinical activity at present, although drug resistance limits its clinical outcome. Growing evidence supports the concept that initial and recurrent GBM may derive from glioblastoma stem cells, which may be responsible for drug resistance. However, the molecular mechanisms underlying this resistance remain to be elucidated. In the present study, a TMZ-resistant GBM cell line, U251R, was developed and subsequently divided into two subpopulations according to the CD133 immunophenotype. No significant difference was identified in the expression of O-6-methylguanine-DNA-methyltransferase (MGMT) between CD133(+) U251R cells and CD133(-) U251R cells, whereas the CD133(+) cell population was more resistant to TMZ-induced growth inhibition and cell death. TMZ achieves its cytotoxic effect by inducing DNA lesions and p53 upregulated modulator of apoptosis (PUMA) is an essential mediator of DNA damage-induced apoptosis independently of p53 status. Therefore, whether PUMA effectively enhances growth suppression and induces apoptosis when combined with TMZ was investigated. Consequently, it was found that adenoviruses expressing wild-type-PUMA not only lead to the apoptosis of CD133(+) U251R cells alone, but also significantly increase their sensitivity toward TMZ by elevating the Bcl-2-associated X protein/B-cell lymphoma-2 ratio without alterations in MGMT expression. Therefore, PUMA may be a suitable target for intervention to improve the therapeutic efficacy of TMZ.
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