Reducing expression of dynamin-related protein 1 increases radiation sensitivity of glioblastoma cells

Abstract

172 words Cheng, 2 -Text: 16 pages, 3732 words Figures, 5 Tables, 1 Cheng, 3 - Translational RelevanceThis study shows that dynamin-related protein 1 (DRP1), an essential 80-kDa GTPase, which is involved in mitochondrial fission, and mitochondrial protein imports, is highly expressed in glioblastoma multiforme (GBM). Moreover, we demonstrate that DRP1 expression is closely associated with radiation sensitivity, cancer progression, and patients' cumulative survival. In vitro, inhibition of DRP1 expression reduced the nuclear entry of DNA repair-associated enzymes, such as ATM, but increased radiation sensitivity and nuclear drug uptakes of glioblastoma cells. More importantly, the silencing of DRP1 induced cellular autophagy. These results indicate that DRP1 overexpression could be a prospective radio-resistant phenotype in GBM and a clinically important target for improving the effectiveness of radiation therapy. AbstractBackground: Dynamin-related protein 1 (DRP1) is a GTPase involved in mitochondrial fission, mitochondrial protein imports, and drug sensitivity, suggesting an association with cancer progression. This study is to evaluate the prognostic significance of DRP1 in glioblastoma multiforme (GBM). Material and Methods: DRP1 expression was measured by immunohistochemistry and Western blotting. Correlations between DRP1 expression and clinicopathological parameters were analyzed by statistical analysis. Differences in survival were compared by a log-rank test.Results: DRP1 expression was detected in 87.2% (41/47) patients with GBM. Patients with higher DRP1 levels had worse survival (p = 0.0398). In vitro, silencing of DRP1 reduced cell proliferation, metastatic potential, and radiation resistance. The addition of shikonin inhibited DRP1 expression and increased drug uptake. Moreover, shikonin reduced the nuclear entry of DNA repair-associated enzymes and increased radiation sensitivity, suggesting that to reduce DRP1 expression could inhibit DNA repair and increase the radiation sensitivity of GBM cells. Conclusion:Our results indicate that DRP1 overexpression is a prospective radio-resistant phenotype in GBM. Therefore, DRP1 could be a potential target for improving the effectiveness of radiation therapy.

DAP3 Is Involved in Modulation of Cellular Radiation Response by RIG-I-Like Receptor Agonist in Human Lung Adenocarcinoma Cells

“…These reports indicate that Drp1 mediates cell death. Conversely, the protective effects of Drp1 on cell death have also been reported [ 33 , 34 , 35 ]. For example, depletion of Drp1 is known to increase apoptosis in human colon cancer cells [ 33 ].…”

“…For example, depletion of Drp1 is known to increase apoptosis in human colon cancer cells [ 33 ]. In addition, Chen et al reported that silencing of Drp1 increased radiosensitivity of UM87MG and T98G human glioblastoma cells [ 34 ]. Furthermore, Akita et al demonstrated that Drp1-knockdown sensitized A375 cells (a human malignant melanoma) and A549 to tumor necrosis factor-related apoptosis-inducing ligand, although Drp1-knockdown by itself did not increase the rate of apoptosis [ 35 ].…”

Exploring neuroadaptive cellular pathways in chronic morphine exposure: An in‐vitro analysis of cabergoline and Mdivi‐1 co‐treatment effects on the autophagy–apoptosis axis

“…Additionally, neither acute nor chronic morphine treatment appears to influence DRP1 expression in nonneural GBM cell lines; however, previous studies suggest that the DRP1 pathway participates actively in facilitating migration and invasion of GBM cells, highlighting its role in proliferation and spread of GBM 66 . Strategies to decrease DRP1 expression could obstruct DNA repair mechanisms while heightening the radiosensitivity of GBM cells 67 . Nevertheless, there exists a noticeable gap in the research regarding this issue.…”

“…66 Strategies to decrease DRP1 expression could obstruct DNA repair mechanisms while heightening the radiosensitivity of GBM cells. 67 Nevertheless, there exists a noticeable gap in the research regarding this issue. The proposed combined treatment offers an opportunity for future studies on pain management in patients with GBM.…”