Downregulating DNA methyltransferase 3B by suppressing the PI3K/Akt signaling pathway enhances the chemosensitivity of glioblastoma to temozolomide.

Autor: Kan W; Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310011, Zhejiang, China., Gao L; The First Clinical Medical College of Zhejiang, Chinese Medical University, Hangzhou, 310053, Zhejiang, China., Chen J; Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310011, Zhejiang, China., Chen L; Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310011, Zhejiang, China., Zhang G; Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310011, Zhejiang, China., Hao B; Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310011, Zhejiang, China., He M; Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310011, Zhejiang, China., Chen X; Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310011, Zhejiang, China., Wang C; Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310011, Zhejiang, China. xh_wangcheng@163.com.
Jazyk: angličtina
Zdroj: Molecular neurobiology [Mol Neurobiol] 2024 Sep; Vol. 61 (9), pp. 7066-7074. Date of Electronic Publication: 2024 Feb 17.
DOI: 10.1007/s12035-024-04041-7
Abstrakt: Glioblastoma (GBM) is the most common malignant brain tumor and has the poorest prognosis attributed to its chemoresistance to temozolomide (TMZ), the first-line drug for treating GBM. TMZ resistance represents a significant obstacle to successful GBM treatment, necessitating the development of new strategies to overcome this resistance and augment the chemosensitivity of GBM cells to TMZ. This study established a TMZ-resistant U251 (U251-TMZ) cell line by exposing it to increasing doses of TMZ in vitro. We focused on the DNA methyltransferase 3B (DNMT3B) gene, phosphorylated Akt (p-Akt), total Akt (t-Akt), phosphorylated PI3K (p-PI3K), and total PI3K (t-PI3K) protein expression. Results showed that the DNMT3B gene was significantly upregulated in the U251-TMZ cell line. The p-Akt and p-PI3K protein expression in U251-TMZ cells was also significantly elevated. Moreover, we found that DNMT3B downregulation was correlated with the increased chemosensitivity of GBM cells to TMZ. LY294002 suppressed the PI3K/Akt signaling pathway, leading to a notable inhibition of PI3K phosphorylation and a significant decrease in DNMT3B expression in U251-TMZ cells. Given that DNMT3B expression is mediated by the PI3K/Akt signaling pathway, its downregulation further increased the chemosensitivity of GBM cells to TMZ and therefore is a promising therapeutic for GBM treatment. Our results suggested that DNMT3B downregulation can inhibit the proliferation of GBM cells and induce GBM cell apoptosis in vitro. In addition, the PI3K/Akt signaling pathway plays an important role in the chemosensitivity of GBM cells to TMZ by regulating DNMT3B expression.
(© 2024. The Author(s).)
Databáze: MEDLINE
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