Mitochondrial protein ATPase family, AAA domain containing 3A correlates with radioresistance in glioblastoma

You, Weir-Chiang; Chiou, Shiow-Her; Huang, Kevin Chih-Yang; Chiang, Shu‐Fen; Yang, Chenglin; Sudhakar, Janaki N.; Lin, Tze–Yi; Chiang, I-Ping; Shen, Chiung‐Chyi; Cheng, Wen-Yu; Lin, Jin-Chin; Shieh, Shwn-Huey; Chow, Kuan‐Chih

doi:10.1093/neuonc/not077

Cited by 42 publications

(59 citation statements)

References 39 publications

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“…Their results strongly suggested that MAM and its associated enzymes, in particular, the DRP1, a GTPase, played a pivotal role in allocating materials, which were essential for maintaining organelle morphology, and DNA integrity of the genome and the mitochondria. Our data supported their results and showed that reducing cytoplasmic DRP-1, either by addition of shikonin or exposure to hypoxia (Supplementary Figures S4A-S4D), might inhibit import of DNA repair-associated enzymes [39,43] and that of mitochondrial biogenesis-and oxidative respiration-related proteins to decrease genomic and mitochondrial DNA stability, which was ultimately reflected in an increased sensitivity to drugs and radiation. (Figure.…”

Section: Discussionsupporting

confidence: 89%

“…Elevation of glucose transport altered mitochondrial metabolism, while the increase of Cheng, 18 -AKR enzymes deactivated TMZ and cisplatin, supporting our findings that some of AKR enzymes were localized on the mitochondria-associated membrane (MAM), the essential organelle that regulated material transports to mitochondria and nucleus [38,39]. Both transportation passages require DRP1, ATAD3A, and mitofusin 2 (Mfn2) [25,42].…”

Section: Discussionsupporting

confidence: 73%

“…In vitro, DRP1 expression correlates with resistant phenotype to radiation and TMZ (T98G cells were more resistant than U87MG cells). Nonetheless, silencing of DRP1 gene increases sensitivity of both U87MG cells (with a methylated MGMT promoter) and T98G cells (with an unmethylated MGMT promoter) to radiation and TMZ, suggesting that methylation status of MGMT promoter may affect expression of DRP1, as well as that of Aldo-keto reductase (AKR) 1C1 and 1C2 [39,40] to enforce radiation phenotype of GBM cells [22] [14,24,25,31]. Binding of DRP1 to the nucleoli could further protect the rRNA-encoding region to maintain genome stability [22], and these events together could regulate cellular activity against cytotoxic agents and radiation.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, the ER also constitutes the outer part of the nuclear envelope as well. It is , therefore, reasonable to anticipate that a decrease of cytoplasmic DRP1 may concurrently damage the mitochondrial membrane and the nuclear envelope, which not only decreases general ATP supply but also reduces nuclear imports of DNA repair-related enzymes [39]. Moreover, elevated nuclear import of DRP1 could consume massive intracellular hHR23A, which would competitively diminish the nuclear import of xeroderma pigmentosum complementation group C (XPC) to delay nucleotide excision repair (NER) that was essential for maintaining genome integrity following the challenge of TMZ or cisplatin [22,39,41,43].…”

Section: Discussionmentioning

confidence: 99%

“…Our previous studies showed that inhibiting intracellular cargo transportation-related enzymes could result in a reduction of nuclear levels of DNA Cheng, 16 -repair-related proteins, such as ataxia-telangiectasia-mutated (ATM) kinase, and an increase of the cytotoxic effect of anticancer drugs and irradiation [22,24,25,39].…”

Section: Shikonin Increases Nuclear Levels Of Anticancer Drugs and Armentioning

confidence: 99%

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

Cheng

Chow

Chiao

et al. 2019

Preprint

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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.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Shikonin Increases Nuclear Levels Of Anticancer Drugs and Armentioning

confidence: 99%

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

Cheng

Chow

Chiao

et al. 2019

Preprint

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Prognostic value of test(s) for O6-methylguanine–DNA methyltransferase (MGMT) promoter methylation for predicting overall survival in people with glioblastoma treated with temozolomide

McAleenan

Kelly

Spiga

et al. 2021

Cochrane Database of Systematic Reviews

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The value of ATAD3A as a potential biomarker for bladder cancer

Liu,

Sun,

Zheng

et al. 2023

Cancer Medicine

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BackgroundBladder cancer (BCa) is a highly malignant tumor, and if left untreated, it can develop severe hematuria and tumor metastasis, thereby endangering the patient's life. The purpose of this paper was to detect the expression of ATAD3A in BCa and research the relationship between ATAD3A and pathological features of bladder cancer and the prognosis of patients.MethodsFirst, the expression of ATAD3A in BCa and normal bladder tissues was analyzed based on the UALCAN and Oncomine public databases. Second, 491 cases of surgically resected bladder cancer specimens and 110 cases of normal adjacent tissues were immunohistochemically stained. The expression of ATAD3A was quantified, and the value and prognosis of ATAD3A as a biomarker of BCa were evaluated.ResultsThe expression of ATAD3A in bladder cancer tissues was higher than that in normal bladder mucosa. High expression of ATAD3A was correlated with patient age, tumor size, number of tumors, distant metastasis, lymph node metastasis, lymphovascular invasion, and TNM stage (p < 0.05). Overexpression of ATAD3A is closely related to cancer patient survival. The mean survival time of bladder cancer patients with high ATAD3A expression was shorter than those with low ATAD3A levels. According to the relative comparing result, the high ATAD3A expression herald reduced overall survival in BCa patients.ConclusionsThe abnormal overexpression of ATAD3A may be related to the initiation and progress of bladder cancer. The upregulation of ATAD3A can be used as an effective indicator to diagnose bladder cancer and predict tumor progression. Furthermore, the combination of information from public databases and the results of clinical sample analysis can help us better understand the mechanism of action of molecular oncogenes in bladder cancer.

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Mitochondrial protein ATPase family, AAA domain containing 3A correlates with radioresistance in glioblastoma

Abstract: Our data suggest that high expression of ATAD3A is an independent biomarker for radioresistance in GBM. ATAD3A could be a potential target for therapy.

Cited by 42 publications

References 39 publications

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

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

Prognostic value of test(s) for O6-methylguanine–DNA methyltransferase (MGMT) promoter methylation for predicting overall survival in people with glioblastoma treated with temozolomide

The value of ATAD3A as a potential biomarker for bladder cancer

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