PT  - JOURNAL ARTICLE
AU  - Wen-Yu Cheng
AU  - Kuan-Chih Chow
AU  - Ming-Tsang Chiao
AU  - Yi-Chin Yang
AU  - Chiung-Chyi Shen
TI  - Reducing expression of dynamin-related protein 1 increases radiation sensitivity of glioblastoma cells
AID  - 10.1101/688861
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 688861
4099  - http://biorxiv.org/content/early/2019/07/01/688861.short
4100  - http://biorxiv.org/content/early/2019/07/01/688861.full
AB  - Background 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.Abbreviations used are: ATAD3A, the ATPase family, AAA domain containing 3A; CIM, confocal immunofluorescence microscopy; DRP1, dynamin-related protein 1; ER, endoplasmic reticulum; GBM, glioblastoma multiforme; hHR23A, human homolog of yeast Rad23 protein A; IDH1, isocitrate dehydrogenase 1; MAM, mitochondria-associated membrane; MGMT, O6-methylguanine-DNA-methyltransferase; SAHA, suberoylanilide hydroxamic acid (vorinostat); TMZ, temozolomideTranslational Relevance This 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.