p53 upregulated modulator of apoptosis sensitizes drug-resistant U251 glioblastoma stem cells to temozolomide through enhanced apoptosis

Jan 28, 2015Molecular medicine reports

Protein p53 increases drug sensitivity in resistant glioblastoma stem cells by boosting cell death with temozolomide

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Abstract

TMZ-resistant GBM cells exhibit increased resistance to chemotherapy despite unchanged MGMT expression.

The CD133+ U251R cell population is more resistant to TMZ-induced growth inhibition and cell death compared to the CD133- population.
PUMA, a mediator of DNA damage-induced apoptosis, may enhance the effectiveness of TMZ when combined with adenoviruses expressing wild-type PUMA.
Adenoviruses expressing wild-type PUMA induce apoptosis in CD133+ U251R cells and significantly increase their sensitivity to TMZ.
The combination of wild-type PUMA and TMZ elevates the ratio of pro-apoptotic to anti-apoptotic proteins without altering MGMT expression.

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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 O6‑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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p53 upregulated modulator of apoptosis sensitizes drug-resistant U251 glioblastoma stem cells to temozolomide through enhanced apoptosis

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