Identification of <i>PDHX</i> as a metabolic target for esophageal squamous cell carcinoma

Inoue, Jun; Kishikawa, Masahiro; Tsuda, Hitoshi; Nakajima, Yasuaki; Asakage, Takahiro; Inazawa, Johji

doi:10.1111/cas.14938

Cited by 13 publications

(10 citation statements)

References 50 publications

(128 reference statements)

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“…Loss of PDH activity or function signifies the cellular transition to the glycolytic state, where pyruvate is converted to lactate in cancer cells, inducing aerobic glycolysis. Thus, PDHX (and PDH complexes in general) effectively exert tumor-suppressive effects by maintaining normal metabolic homeostasis [ 75 ]. Eastlack et al found that miR-27b inhibited the expression of the PDH complex by targeting the 3'UTR of PDHX , resulting in specific metabolic dysregulation.…”

Section: Non-coding Rna and Breast Cancer Glucose Metabolismmentioning

confidence: 99%

Metabolism-regulating non-coding RNAs in breast cancer: roles, mechanisms and clinical applications

Xu,

Wang,

Zhao

et al. 2024

J Biomed Sci

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Breast cancer is one of the most common malignancies that pose a serious threat to women's health. Reprogramming of energy metabolism is a major feature of the malignant transformation of breast cancer. Compared to normal cells, tumor cells reprogram metabolic processes more efficiently, converting nutrient supplies into glucose, amino acid and lipid required for malignant proliferation and progression. Non-coding RNAs(ncRNAs) are a class of functional RNA molecules that are not translated into proteins but regulate the expression of target genes. NcRNAs have been demonstrated to be involved in various aspects of energy metabolism, including glycolysis, glutaminolysis, and fatty acid synthesis. This review focuses on the metabolic regulatory mechanisms and clinical applications of metabolism-regulating ncRNAs involved in breast cancer. We summarize the vital roles played by metabolism-regulating ncRNAs for endocrine therapy, targeted therapy, chemotherapy, immunotherapy, and radiotherapy resistance in breast cancer, as well as their potential as therapeutic targets and biomarkers. Difficulties and perspectives of current targeted metabolism and non-coding RNA therapeutic strategies are discussed.

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Section: Non-coding Rna and Breast Cancer Glucose Metabolismmentioning

confidence: 99%

Metabolism-regulating non-coding RNAs in breast cancer: roles, mechanisms and clinical applications

Xu,

Wang,

Zhao

et al. 2024

J Biomed Sci

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“…Results of our study clarify possible mechanisms of glutamine and glucose deprivations on the proliferation/surviving of ERN1 knockdown glioma cells through specific changes in the expression profile of genes encoding important enzymes of PDH complex (Babady et al 2007;Mathias et al 2014;Eastlack et al 2018;Yonashiro et al 2018;Jin et al 2016;Yetkin-Arik et al 2019;Cai et al 2020;Shin et al 2020;Inoue et al 2021;Zaher et al 2021).…”

Section: Discussionmentioning

confidence: 62%

“…We also showed that PDHX is resistant to glutamine deprivation and these results also agree well with its essential role in the functional activity of a PDH complex (Eastlack et al 2018). Recently, it was shown that PDHX is a metabolically essential gene for the cell growth because its expression is required for the maintenance of PDH activity and the production of ATP and its knock-down inhibited the proliferation of cancer cells and in vivo the tumor growth (Inoue et al 2021).…”

Section: Discussionmentioning

confidence: 99%

“…The silencing of PDHX by miR-27b leads to an altered metabolic configuration that is better to cell proliferation, thereby promoting breast cancer progression (Eastlack et al 2018). Therefore, PDHX is a metabolically essential gene for the cell growth because its expression is required for the maintenance of PDH activity and the production of ATP and its knockdown inhibited the proliferation of cancer cells and in vivo tumor growth (Inoue et al 2021).…”

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confidence: 99%

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ERN1 dependent impact of glutamine and glucose deprivations on the pyruvate dehydrogenase genes expression in glioma cells

Shatokhina

Khita

Minchenko

et al. 2022

Endocrine Regulations

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Objective. The aim of the present study was to investigate the expression of pyruvate dehydrogenase genes such as PDHA1, PDHB, DLAT, DLD, and PDHX in U87 glioma cells in response to glutamine and glucose deprivations in control glioma cells and endoplasmic reticulum to nucleus signaling 1 (ERN1) knockdown cells, the major endoplasmic reticulum (ER) stress signaling pathway, to find out whether there exists a possible dependence of these important regulatory genes expression on both glutamine and glucose supply as well as ERN1 signaling. Methods. The expression level of PDHA1, PDHB, DLAT, DLD, and PDHX genes was studied by real-time quantitative polymerase chain reaction in control U87 glioma cells (transfected by empty vector) and cells with inhibition of ERN1(transfected by dnERN1) after cells exposure to glucose and glutamine deprivations. Results. The data showed that the expression level of PDHA1, PDHB, DLAT, and DLD genes was down-regulated (more profound in PDHB gene) in control glioma cells treated with glutamine deprivation. At the same time, ERN1 knockdown modified the impact of glutamine deprivation on the expression level of all these genes in glioma cells: suppressed the sensitivity of PDHB and DLD genes expression and removed the impact of glutamine deprivation on the expression of PDHA1 and DLAT genes. Glucose deprivation did not significantly change the expression level of all studied genes in control glioma cells, but ERN1 knockdown is suppressed the impact of glucose deprivation on PDHX and DLD genes expression and significantly enhanced the expression of PDHA1 and PDHB genes. No significant changes were observed in the sensitivity of PDHX gene expression to glutamine deprivation neither in control nor ERN1 knock-down glioma cells. The knock-down of ERN1 removed the sensitivity of DLAT gene expression to glucose deprivation. Conclusion. The results of this investigation demonstrate that the exposure of control U87 glioma cells under glutamine deprivation significantly affected the expression of PDHA1, PDHB, DLAT, and DLD genes in a gene specific manner and that impact of glutamine deprivation was modified by inhibition of the ER stress signaling mediated by ERN1. At the same time, glucose deprivation affected the expression of PDHA1, PDHB, PDHX, and DLD genes in ERN1 knockdown glioma cells only. Thus, the expression of pyruvate dehydrogenase genes under glutamine and glucose deprivation conditions appears to be controlled by the ER stress signaling through ERN1.

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“…Small molecule PDH inhibitors have been proven effective in pre-clinical models. CPI-613, a PDH inhibitor has been shown to inhibit the proliferation of cancer stem cells (CSCs) in vitro and the growth of ESCC xenograft tumors in vivo [34].…”

Section: Pyruvate Dehydrogenasementioning

confidence: 99%

Overcoming Radiation Resistance in Gliomas by Targeting Metabolism and DNA Repair Pathways

Wang

Palmer

Siedow

et al. 2022

IJMS

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Gliomas represent a wide spectrum of brain tumors characterized by their high invasiveness, resistance to chemoradiotherapy, and both intratumoral and intertumoral heterogeneity. Recent advances in transomics studies revealed that enormous abnormalities exist in different biological layers of glioma cells, which include genetic/epigenetic alterations, RNA expressions, protein expression/modifications, and metabolic pathways, which provide opportunities for development of novel targeted therapeutic agents for gliomas. Metabolic reprogramming is one of the hallmarks of cancer cells, as well as one of the oldest fields in cancer biology research. Altered cancer cell metabolism not only provides energy and metabolites to support tumor growth, but also mediates the resistance of tumor cells to antitumor therapies. The interactions between cancer metabolism and DNA repair pathways, and the enhancement of radiotherapy sensitivity and assessment of radiation response by modulation of glioma metabolism are discussed herein.

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Identification of PDHX as a metabolic target for esophageal squamous cell carcinoma

Cited by 13 publications

References 50 publications

Metabolism-regulating non-coding RNAs in breast cancer: roles, mechanisms and clinical applications

Metabolism-regulating non-coding RNAs in breast cancer: roles, mechanisms and clinical applications

ERN1 dependent impact of glutamine and glucose deprivations on the pyruvate dehydrogenase genes expression in glioma cells

Overcoming Radiation Resistance in Gliomas by Targeting Metabolism and DNA Repair Pathways

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