Cyclooxygenase-2-Mediated Up-Regulation of Mitochondrial Transcription Factor A Mitigates the Radio-Sensitivity of Cancer Cells

Tang, Fan; Zhang, Rui; Wang, Jun

doi:10.3390/ijms20051218

Cited by 13 publications

(7 citation statements)

References 47 publications

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“…In the current study, COX-2-knockdown based on CRISPR/Cas9 suppressed mito-COX-2/p-Drp1 Ser616 interaction and increased the chemosensitivity of HCC. Consistent with our results, Tang et al found that inhibition of COX-2 by NS-398 sensitized cancer cells to radiotherapy via the downregulation of the p38/Drp1/TFAM signaling axis, mediating mitochondrial fission [49]. Suppression of Drp1-driven mitochondrial fission enhanced the sensitivity of hypoxic ovarian cancer cells to cDDP [61].…”

Section: Discussionsupporting

confidence: 92%

“…It has been shown that the multi-kinase framework including ERK/AKT and CDK2 promotes cell proliferation of A549 and HCC827 cells by activating Drp1 [48]. Tang et al [49] found that COX-2 contributed to the upregulation of mitochondrial transcription factor A (TFAM), mediated by p38-MAPK activation, and the subsequent enhancement of Drp1-dependent mitochondrial fission in human osteosarcoma U-2 OS and cervical cancer HeLa cells. However, the mechanisms remain to be elucidated for how p-Drp1 Ser616 is regulated in HCC cells with high COX-2 expression.…”

Section: Discussionmentioning

confidence: 99%

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Targeting Mitochondrial COX-2 Enhances Chemosensitivity via Drp1-Dependent Remodeling of Mitochondrial Dynamics in Hepatocellular Carcinoma

Che

et al. 2022

Cancers

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Mitochondria are highly dynamic organelles and undergo constant fission and fusion, which are both essential for the maintenance of cell physiological functions. Dysregulation of dynamin-related protein 1 (Drp1)-dependent mitochondrial dynamics is associated with tumorigenesis and the chemotherapeutic response in hepatocellular carcinoma (HCC). The enzyme cyclooxygenase-2 (COX-2) is overexpressed in most cancer types and correlates with a poor prognosis. However, the roles played by the translocation of mitochondrial COX-2 (mito-COX-2) and the interaction between mito-COX-2 and Drp1 in chemotherapeutic responses remain to be elucidated in the context of HCC. Bioinformatics analysis, paired HCC patient specimens, xenograft nude mice, immunofluorescence, transmission electron microscopy, molecular docking, CRISPR/Cas9 gene editing, proximity ligation assay, cytoplasmic and mitochondrial fractions, mitochondrial immunoprecipitation assay, and flow cytometry analysis were performed to evaluate the underlying mechanism of how mito-COX-2 and p-Drp1Ser616 interaction regulates the chemotherapeutic response via mitochondrial dynamics in vitro and in vivo. We found that COX-2 and Drp1 were frequently upregulated and confer a poor prognosis in HCC. We also found that the proportion of mito-COX-2 and p-Drp1Ser616 was increased in HCC cell lines. In vitro, we demonstrated that the enhanced mitochondrial translocation of COX-2 promotes its interaction with p-Drp1Ser616 via PTEN-induced putative kinase 1 (PINK1)-mediated Drp1 phosphorylation activation. This increase was associated with higher colony formation, cell proliferation, and mitochondrial fission. These findings were confirmed by knocking down COX-2 in HCC cells using CRISPR/Cas9 technology. Furthermore, inhibition of Drp1 using pharmacologic inhibitors (Mdivi-1) or RNA interference (siDNM1L) decreased mito-COX-2/p-Drp1Ser616 interaction-mediated mitochondrial fission, and increased apoptosis in HCC cells treated with platinum drugs. Moreover, inhibiting mito-COX-2 acetylation with the natural phytochemical resveratrol resulted in reducing cell proliferation and mitochondrial fission, occurring through upregulation of mitochondrial deacetylase sirtuin 3 (SIRT3), which, in turn, increased the chemosensitivity of HCC to platinum drugs in vitro and in vivo. Our results suggest that targeting interventions to PINK1-mediated mito-COX-2/p-Drp1Ser616-dependent mitochondrial dynamics increases the chemosensitivity of HCC and might help us to understand how to use the SIRT3-modulated mito-COX-2/p-Drp1Ser616 signaling axis to develop an effective clinical intervention in hepatocarcinogenesis.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Targeting Mitochondrial COX-2 Enhances Chemosensitivity via Drp1-Dependent Remodeling of Mitochondrial Dynamics in Hepatocellular Carcinoma

Che

et al. 2022

Cancers

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“…Similar to the functions of TEFM in HCC, another mitochondrial transcription regulator TFAM also has been reported to induce G1 cell cycle transition, but inhibit cell apoptosis in glioma and non-small cell lung cancers 17 , 20 . Besides the tumor growth promoting role, increased TFAM also confers resistance to ionizing radiation in several types of malignances 17 , 21 , 22 , further supporting an inhibitory role for TFAM in tumor cell apoptosis. Meanwhile, we also tested the effect of TEFM on metastasis of HCC and found that TEFM knockdown decreased the migration and invasion of SNU-354 and SNU-739 cells, while TEFM over-expression enhanced the migration and invasion of HUH-7 and HLF cells.…”

Section: Discussionmentioning

confidence: 86%

Elevated TEFM expression promotes growth and metastasis through activation of ROS/ERK signaling in hepatocellular carcinoma

et al. 2021

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TEFM (transcription elongation factor of mitochondria) has been identified as a novel nuclear-encoded transcription elongation factor in the transcription of mitochondrial genome. Our bioinformatics analysis of TCGA data revealed an aberrant over-expression of TEFM in hepatocellular carcinoma (HCC). We analyzed its biological effects and clinical significance in this malignancy. TEFM expression was analyzed by quantitative real-time PCR, western blot, and immunohistochemistry analysis in HCC tissues and cell lines. The effects of TEFM on HCC cell growth and metastasis were determined by cell proliferation, colony formation, flow cytometric cell cycle and apoptosis, migration, and invasion assays. TEFM expression was significantly increased in HCC tissues mainly caused by down-regulation of miR-194-5p. Its increased expression is correlated with poor prognosis of HCC patients. TEFM promoted HCC growth and metastasis both in vitro and in vivo by promoting G1–S cell transition, epithelial-to-mesenchymal transition (EMT), and suppressing cell apoptosis. Mechanistically, TEFM exerts its tumor growth and metastasis promoting effects at least partly through increasing ROS production and subsequently by activation of ERK signaling. Our study suggests that TEFM functions as a vital oncogene in promoting growth and metastasis in HCC and may contribute to the targeted therapy of HCC.

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“…The activities of phospholipase A2, COX and PGE 2 synthases are essential to the biosynthesis of PGE 2 . A previous study demonstrated that COX-2 is rapidly induced by oncogenes, growth factors, cytokines and tumor promoters, and serves an important role in the development of cancer (34). Furthermore, COX-2 regulates tumor growth by binding to its corresponding receptors through various downstream prostate products, instead of acting as a signal transduction kinase.…”

Section: Discussionmentioning

confidence: 99%

E6‑regulated overproduction of prostaglandin�E2 may inhibit migration of dendritic cells in human papillomavirus 16‑positive cervical lesions

et al. 2020

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Continuous human papillomavirus (HPV) infection is a critical cause of cervical lesions; however, the specific mechanism is currently not clear. E6 is one of the most important oncoproteins associated with HPV, which regulates synthases in the production of prostaglandin E2 (PGE 2 ). Notably, PGE 2 has been reported to be upregulated in cervical lesions. An insufficient number of mature dendritic cells (DCs), which is unable to cause an effective immune response, is an important cause of cervical lesions. Therefore, this study explored the possible causes of HPV16-positive cervical lesions by identifying the relationship between E6, PGE 2 and DCs. Firstly, the distribution and status of DCs in clinical biopsy specimens and animal models were analyzed with immunohistochemistry and flow cytometry, which demonstrated that the migratory ability of DCs was inhibited in HPV16-positive cervical lesions. Furthermore, using immunohistochemistry, western blotting and ELISA, it was revealed that as the degree of cervical lesions increased, the expression of PGE 2 and its synthases increased. Subsequently, as determined using Transwell and 3D migration assays, it was revealed that a high concentration of PGE 2 inhibited the migration of DCs, which may explain the phenomenon observed in cervical lesions. Notably, E6 was identified to regulate PGE 2 expression. The in vivo experiments indicated that E6 may increase the expression levels of PGE 2 in cervical lesions, which could eventually induce inhibition of the migration of DCs. In conclusion, the present study suggested that E6 regulated overproduction of PGE 2 , which may induce inhibition of DC migration in HPV16-positive cervical lesions.

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Cyclooxygenase-2-Mediated Up-Regulation of Mitochondrial Transcription Factor A Mitigates the Radio-Sensitivity of Cancer Cells

Cited by 13 publications

References 47 publications

Targeting Mitochondrial COX-2 Enhances Chemosensitivity via Drp1-Dependent Remodeling of Mitochondrial Dynamics in Hepatocellular Carcinoma

Targeting Mitochondrial COX-2 Enhances Chemosensitivity via Drp1-Dependent Remodeling of Mitochondrial Dynamics in Hepatocellular Carcinoma

Elevated TEFM expression promotes growth and metastasis through activation of ROS/ERK signaling in hepatocellular carcinoma

E6‑regulated overproduction of prostaglandin�E2 may inhibit migration of dendritic cells in human papillomavirus 16‑positive cervical lesions

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