DRP1 contributes to head and neck cancer progression and induces glycolysis through modulated FOXM1/MMP12 axis

Huang, Tai-Lin; Chang, Chuang–Rung; Chien, Chih‐Yen; Huang, Gong-Kai; Chen, Yifan; Su, Li-Jen; Tsai, Huei‐Ting; Lin, Yu‐Sheng; Fang, Fu‐Min; Chen, Chang‐Han

doi:10.1002/1878-0261.13212

Cited by 20 publications

(11 citation statements)

References 70 publications

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“…High glucose levels can increase the expression of DRP1, resulting in cell dysfunction and promoting the migration and invasion of endometrial cancer cells ( Guo J. et al, 2020 ). The high expression of DRP1 was correlated with poor survival of head and neck cancer patients ( Huang T. L. et al, 2022 ). DRP1 deletion can affect aerobic glycolysis and suppress tumor growth and metastasis ( Huang T. L. et al, 2022 ).…”

Section: Altered Mitochondrial Dynamics Associated With Tumorigenesismentioning

confidence: 99%

“…The high expression of DRP1 was correlated with poor survival of head and neck cancer patients ( Huang T. L. et al, 2022 ). DRP1 deletion can affect aerobic glycolysis and suppress tumor growth and metastasis ( Huang T. L. et al, 2022 ). FIS1 is overexpressed in GC, and its expression is correlated with cancer metastasis ( Karimi et al, 2022 ).…”

Section: Altered Mitochondrial Dynamics Associated With Tumorigenesismentioning

confidence: 99%

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Non-coding RNAs regulate mitochondrial dynamics in the development of gastric cancer

Chen

Wei²,

Huang³

et al. 2023

Front. Mol. Biosci.

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Gastric cancer (GC) is a malignant cancer that reduces life expectancy worldwide. Although treatment strategies have improved, patients with GC still have poor prognoses. Hence, it is necessary to understand the molecular mechanisms of GC and to find new therapeutic targets. Mitochondrial dynamics and mitochondrial dysfunction are associated with cancer cell growth and progression. Numerous studies have reported that non-coding RNAs (ncRNAs) can participate in the occurrence and development of GC by regulating mitochondrial dynamics. Elucidating the crosstalk between ncRNAs and mitochondria would be helpful in preventing and treating GC. Herein, we review and summarize the functions of oncogenes and tumor suppressors in suppressing ncRNAs and regulating mitochondrial dynamics in GC tumor growth, proliferation, invasion and metastasis. This review provides new insights into the pathogenesis of and intervention for GC.

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Section: Altered Mitochondrial Dynamics Associated With Tumorigenesismentioning

confidence: 99%

Section: Altered Mitochondrial Dynamics Associated With Tumorigenesismentioning

confidence: 99%

Non-coding RNAs regulate mitochondrial dynamics in the development of gastric cancer

Chen

Wei²,

Huang³

et al. 2023

Front. Mol. Biosci.

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“…Previous studies have shown that FOXM1 is abundantly expressed in NSCLC and various other cancer (18, 19). Moreover, FOXM1 overexpression was involved in cell cycle, apoptosis and DNA repair regulation, thereby facilitating tumorigenesis and chemoradioresistance through different mechanisms (18,(20)(21)(22)(23).…”

Section: Introductionmentioning

confidence: 99%

SPIN1 accelerates tumorigenesis and confers radioresistance of non-small cell lung cancer via orchestrating the FOXO3a/FOXM1 axis

Zhong,

Fang,

Zou

et al. 2023

Preprint

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Background Radioresistance is a predominant obstacle of effective treatments in non-small cell lung cancer (NSCLC), while the underlying mechanism remains incompletely elucidated. Spindlin 1(SPIN1) has been reported to participate in tumor initiation and progression. Herein, this study aims to explore the role and mechanism of SPIN1 in NSCLC progression and radioresistance.Methods Bioinformatics analysis, immunohistochemistry (IHC) and western blotting were performed to test SPIN1 expression in NSCLC samples and cell lines. The carcinogenic role of SPIN1 was evaluated by cell growth and proliferation, EdU staining, transwell and colony formation assays. Besides, the radiosensitivity of NSCLC cells was determined by clonogenic cell survival, neutral comet and γ-H2AX and Rad51 foci formation assays. Xenograft tumor model was constructed to access the effects of SPIN1 on tumorigenesis and radiosensitivity. RNA sequencing, quantitative real-time PCR, CHX and ubiquitination assays were applied to elucidate the correlation between SPIN1 and FOXO3a-FOXM1 axis.Results We found that SPIN1 was highly expressed in NSCLC tissues and cell lines compared with corresponding controls. And SPIN1 overexpression was closely correlated with disease progression and poor prognosis in NSCLC patients. Functionally, depletion of SPIN1 impaired cell proliferation, delayed cell cycle progression and suppressed migration and invasion. Moreover, SPIN1 knockdown reduced the clonogenic capacity, impaired double-strand break (DSB) repair and enhanced NSCLC radiosensitivity. Mechanistically, forkhead box M1 (FOXM1) was identified as a key downstream effector of SPIN1 in NSCLC cells. Furthermore, SPIN1 facilitates MDM2 mediated FOXO3a ubiquitination and degradation, leading to FOXM1 upregulation. More convincingly, reintroduction of FOXM1 markedly abolished the inhibitory effects and elevated radiosensitivity induced by SPIN1 depletion.Conclusion Our results suggest that the SPIN1-MDM2-FOXO3a/FOXM1 signaling axis is essential for NSCLC progression and radioresistance, and it could serve as therapeutic targets in irradiation-resistance NSCLC.

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“…Defects in mitochondrial dynamics have been also reported in hematological malignancies, as T-cell acute lymphoblastic leukemia and MM [ 15 , 16 ], which enhance the expression and/or activity of fission proteins, like Drp1, to promote survival and resistance to chemotherapy. On this basis, targeting Drp1 holds therapeutic potential in cancer [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Targeting of mitochondrial fission through natural flavanones elicits anti-myeloma activity

Torcasio,

Gallo Cantafio,

Veneziano

et al. 2024

J Transl Med

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Background Mitochondrial alterations, often dependent on unbalanced mitochondrial dynamics, feature in the pathobiology of human cancers, including multiple myeloma (MM). Flavanones are natural flavonoids endowed with mitochondrial targeting activities. Herein, we investigated the capability of Hesperetin (Hes) and Naringenin (Nar), two aglycones of Hesperidin and Naringin flavanone glycosides, to selectively target Drp1, a pivotal regulator of mitochondrial dynamics, prompting anti-MM activity. Methods Molecular docking analyses were performed on the crystallographic structure of Dynamin-1-like protein (Drp1), using Hes and Nar molecular structures. Cell viability and apoptosis were assessed in MM cell lines, or in co-culture systems with primary bone marrow stromal cells, using Cell Titer Glo and Annexin V-7AAD staining, respectively; clonogenicity was determined using methylcellulose colony assays. Transcriptomic analyses were carried out using the Ion AmpliSeq™ platform; mRNA and protein expression levels were determined by quantitative RT-PCR and western blotting, respectively. Mitochondrial architecture was assessed by transmission electron microscopy. Real time measurement of oxygen consumption was performed by high resolution respirometry in living cells. In vivo anti-tumor activity was evaluated in NOD-SCID mice subcutaneously engrafted with MM cells. Results Hes and Nar were found to accommodate within the GTPase binding site of Drp1, and to inhibit Drp1 expression and activity, leading to hyperfused mitochondria with reduced OXPHOS. In vitro, Hes and Nar reduced MM clonogenicity and viability, even in the presence of patient-derived bone marrow stromal cells, triggering ER stress and apoptosis. Interestingly, Hes and Nar rewired MM cell metabolism through the down-regulation of master transcriptional activators (SREBF-1, c-MYC) of lipogenesis genes. An extract of Tacle, a Citrus variety rich in Hesperidin and Naringin, was capable to recapitulate the phenotypic and molecular perturbations of each flavanone, triggering anti-MM activity in vivo. Conclusion Hes and Nar inhibit proliferation, rewire the metabolism and induce apoptosis of MM cells via antagonism of the mitochondrial fission driver Drp1. These results provide a framework for the development of natural anti-MM therapeutics targeting aberrant mitochondrial dependencies.

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DRP1 contributes to head and neck cancer progression and induces glycolysis through modulated FOXM1/MMP12 axis

Cited by 20 publications

References 70 publications

Non-coding RNAs regulate mitochondrial dynamics in the development of gastric cancer

Non-coding RNAs regulate mitochondrial dynamics in the development of gastric cancer

SPIN1 accelerates tumorigenesis and confers radioresistance of non-small cell lung cancer via orchestrating the FOXO3a/FOXM1 axis

Targeting of mitochondrial fission through natural flavanones elicits anti-myeloma activity

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