Targeting Mitochondrial Metabolism to Reverse Radioresistance: An Alternative to Glucose Metabolism

Bian, Chenbin; Zheng, Zhuangzhuang; Su, Jing; Wang, Huanhuan; Chang, Sitong; Xin, Ying; Jiang, Xin

doi:10.3390/antiox11112202

Cited by 13 publications

(15 citation statements)

References 147 publications

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“…Consequently, metabolic changes induced by radiation may correlate with the radiation sensitivity of tumor cells. Studies have shown a close association between glucose metabolism and radioresistance [ 30 ]. Radioresistant tumor cells often exhibit increased glucose metabolism.…”

Section: Discussionmentioning

confidence: 99%

TAB182 regulates glycolytic metabolism by controlling LDHA transcription to impact tumor radiosensitivity

Chen,

Xie,

et al. 2024

Cell Death Dis

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Metabolic reprogramming, a hallmark of cancer, is closely associated with tumor development and progression. Changes in glycolysis play a crucial role in conferring radiation resistance to tumor cells. How radiation changes the glycolysis status of cancer cells is still unclear. Here we revealed the role of TAB182 in regulating glycolysis and lactate production in cellular response to ionizing radiation. Irradiation can significantly stimulate the production of TAB182 protein, and inhibiting TAB182 increases cellular radiosensitivity. Proteomic analysis indicated that TAB182 influences several vital biological processes, including multiple metabolic pathways. Knockdown of TAB182 results in decreased lactate production and increased pyruvate and ATP levels in cancer cells. Moreover, knocking down TAB182 reverses radiation-induced metabolic changes, such as radioresistant-related lactate production. TAB182 is necessary for activating LDHA transcription by affecting transcription factors SP1 and c-MYC; its knockdown attenuates the upregulation of LDHA by radiation, subsequently suppressing lactate production. Targeted suppression of TAB182 significantly enhances the sensitivity of murine xenograft tumors to radiotherapy. These findings advance our understanding of glycolytic metabolism regulation in response to ionizing radiation, which may offer significant implications for developing new strategies to overcome tumor radioresistance.

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Section: Discussionmentioning

confidence: 99%

TAB182 regulates glycolytic metabolism by controlling LDHA transcription to impact tumor radiosensitivity

Chen,

Xie,

et al. 2024

Cell Death Dis

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“…Alteration of cellular energy and redox status via mitochondrial metabolism, a process known as mitochondrial metabolic reprogramming, has been shown to be associated with cancer progression [ 61 , 62 ]. As a result, targeting mitochondria by inhibiting mitochondrial complexes presents a novel therapeutic strategy for cancer [ 63 , 64 ]. Our in vitro data showed that IL-1RA overexpression increased the rate of mitochondrial oxidative metabolism and inhibition of mitochondrial electron transfer complexes, including the use of conventional compound inhibitors (e.g., metformin, phenformin, rotenone, or antimycin A [ 39 , 65 ]) and novel peptide inhibitors (e.g., CT20 [ 66 ] or MITOx20 [ 67 ]), suppressed IL-1RA-promoted malignant behaviors of OSCC cells.…”

Section: Discussionmentioning

confidence: 99%

IL-1RA promotes oral squamous cell carcinoma malignancy through mitochondrial metabolism-mediated EGFR/JNK/SOX2 pathway

et al. 2023

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Background Interleukin-1 receptor antagonist (IL-1RA), a member of the IL-1 family, has diverse roles in cancer development. However, the role of IL-1RA in oral squamous cell carcinoma (OSCC), in particular the underlying mechanisms, remains to be elucidated. Methods Tumor tissues from OSCC patients were assessed for protein expression by immunohistochemistry. Patient survival was evaluated by Kaplan–Meier curve analysis. Impact of differential IL-1RA expression on cultured OSCC cell lines was assessed in vitro by clonogenic survival, tumorsphere formation, soft agar colony formation, and transwell cell migration and invasion assays. Oxygen consumption rate was measured by Seahorse analyzer or multi-mode plate reader. PCR array was applied to screen human cancer stem cell-related genes, proteome array for phosphorylation status of kinases, and Western blot for protein expression in cultured cells. In vivo tumor growth was investigated by orthotopic xenograft in mice, and protein expression in xenograft tumors assessed by immunohistochemistry. Results Clinical analysis revealed that elevated IL-1RA expression in OSCC tumor tissues was associated with increased tumor size and cancer stage, and reduced survival in the patient group receiving adjuvant radiotherapy compared to the patient group without adjuvant radiotherapy. In vitro data supported these observations, showing that overexpression of IL-1RA increased OSCC cell growth, migration/invasion abilities, and resistance to ionizing radiation, whereas knockdown of IL-1RA had largely the opposite effects. Additionally, we identified that EGFR/JNK activation and SOX2 expression were modulated by differential IL-1RA expression downstream of mitochondrial metabolism, with application of mitochondrial complex inhibitors suppressing these pathways. Furthermore, in vivo data revealed that treatment with cisplatin or metformin—a mitochondrial complex inhibitor and conventional therapy for type 2 diabetes—reduced IL-1RA-associated xenograft tumor growth as well as EGFR/JNK activation and SOX2 expression. This inhibitory effect was further augmented by combination treatment with cisplatin and metformin. Conclusions The current study suggests that IL-1RA promoted OSCC malignancy through mitochondrial metabolism-mediated EGFR/JNK activation and SOX2 expression. Inhibition of this mitochondrial metabolic pathway may present a potential therapeutic strategy in OSCC.

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“…However, SOD1 overexpression confers radioresistance in human glioma cells by suppressing irradiation-induced late ROS accumulation. These contradictory results may be due to the dual role of ROS in which the difference in ROS levels is dominant ( Bian et al, 2022b ). The copper chaperone for COX17, which is located in the cytoplasm and mitochondrial membrane space (IMS), is another copper metallochaperone involved in electron transfer in the oxidative respiratory chains ( Lyons et al, 2012 ).…”

Section: Regulation Of Copper Homeostasis In Mammalian Cellsmentioning

confidence: 99%

Copper homeostasis and cuproptosis in tumor pathogenesis and therapeutic strategies

Bian,

Zheng,

et al. 2023

Front. Pharmacol.

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Copper is an indispensable micronutrient for the development and replication of all eukaryotes, and its redox properties are both harmful and beneficial to cells. An imbalance in copper homeostasis is thought to be involved in carcinogenesis. Importantly, cancer cell proliferation, angiogenesis, and metastasis cannot be separated from the effects of copper. Cuproposis is a copper-dependent form of cell death that differs from other existing modalities of regulatory cell death. The role of cuproptosis in the pathogenesis of the nervous and cardiovascular systems has been widely studied; however, its impact on malignant tumors is yet to be fully understood from a clinical perspective. Exploring signaling pathways related to cuproptosis will undoubtedly provide a new perspective for the development of anti-tumor drugs in the future. Here, we systematically review the systemic and cellular metabolic processes of copper and the regulatory mechanisms of cuproptosis in cancer. In addition, we discuss the possibility of targeting copper ion drugs to prolong the survival of cancer patients, with an emphasis on the most representative copper ionophores and chelators. We suggest that attention should be paid to the potential value of copper in the treatment of specific cancers.

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Targeting Mitochondrial Metabolism to Reverse Radioresistance: An Alternative to Glucose Metabolism

Cited by 13 publications

References 147 publications

TAB182 regulates glycolytic metabolism by controlling LDHA transcription to impact tumor radiosensitivity

TAB182 regulates glycolytic metabolism by controlling LDHA transcription to impact tumor radiosensitivity

IL-1RA promotes oral squamous cell carcinoma malignancy through mitochondrial metabolism-mediated EGFR/JNK/SOX2 pathway

Copper homeostasis and cuproptosis in tumor pathogenesis and therapeutic strategies

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