Cell Metabolism and DNA Repair Pathways: Implications for Cancer Therapy

Sobanski, Thais; Rose, Maddison; Suraweera, Amila; O’Byrne, Kenneth J.; Richard, Derek J.; Bolderson, Emma

doi:10.3389/fcell.2021.633305

Cited by 48 publications

(42 citation statements)

References 127 publications

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“…Efficient glucose utilization by malignant tumors is associated with high proliferation, aggressiveness, and self-renewal capacity [ 61 ]. Numerous studies have demonstrated a link between DNA damage repair and glycolysis, which are interdependent and promote the uncontrolled proliferation and survival of tumor cells [ 62 ]. Thomas M Ashton et al revealed that oxidative phosphorylation is commonly upregulated in tumor cells with high metastatic and tumorigenic potential, including LUAD [ 63 ].…”

Section: Discussionmentioning

confidence: 99%

A novel pyroptosis-related lncRNA signature for prognostic prediction in patients with lung adenocarcinoma

et al. 2021

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Lung adenocarcinoma (LUAD) has been the major cause of tumor-associated mortality in recent years and has a poor prognosis. Pyroptosis is regulated via the activation of inflammasomes and participates in tumorigenesis. However, the effects of pyroptosis-related lncRNAs (PRlncRNAs) on LUAD have not yet been completely elucidated. Therefore, we attempted to systematically explore patterns of cell pyroptosis to establish a novel signature for predicting LUAD survival. Based on TCGA database, we set up a prognostic model by incorporating PRlncRNAs with differential expression using Cox regression and LASSO regression. Kaplan-Meier analysis was conducted to compare the survival of LUAD patients. We further simplified the risk model and created a nomogram to enhance the prediction of LUAD prognosis. Altogether, 84 PRlncRNAs with differential expression were discovered. Subsequently, a new risk model was constructed based on five PRlncRNAs, GSEC, FAM83A-AS1, AL606489.1, AL034397.3 and AC010980.2. The proposed signature exhibited good performance in prognostic prediction and was related to immunocyte infiltration. The nomogram exactly forecasted the overall survival of patients and had excellent clinical utility. In the present study, the five-lncRNA prognostic risk signature and nomogram are trustworthy and effective indicators for predicting the prognosis of LUAD.

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Section: Discussionmentioning

confidence: 99%

A novel pyroptosis-related lncRNA signature for prognostic prediction in patients with lung adenocarcinoma

et al. 2021

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“…Furthermore, the regulation of DNA-PK activity by ALDOA and vice versa, supports the possibility of a feedback loop leading to crosstalk between regulation of DNA repair and metabolism, which merits further investigation. Importantly, various metabolic factors including fumarase, glutamine synthase, ATP-citrate lyase and PKM2 have been shown to play a critical role in DNA repair pathways including NHEJ and homologous recombination (HR) [48].…”

Section: Combination Of Dna-pk and Glycolysis Inhibitor Decreases Proliferation In Crpcmentioning

confidence: 99%

A Novel Role for DNA-PK in Metabolism by Regulating Glycolysis in Castration-Resistant Prostate Cancer

Dylgjeri

Kothari

Shafi

et al. 2022

Clinical Cancer Research

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Purpose: DNA-dependent kinase catalytic subunit (DNA-PKcs, herein referred as DNA-PK) is a multifunctional kinase of high cancer relevance. DNA-PK is deregulated in multiple tumor types, including prostate cancer (PCa), and is associated with poor outcomes. DNA-PK was previously nominated as a therapeutic target and DNA-PK inhibitors are currently undergoing clinical investigation. While DNA-PK is well studied in DNA repair and transcriptional regulation, much remains to be understood about the way by which DNA-PK drives aggressive disease phenotypes.Experimental Design: Here, unbiased proteomic and metabolomic approaches in clinically relevant tumor models uncovered a novel role of DNA-PK in metabolic regulation of cancer progression. DNA-PK regulation of metabolism was interrogated using pharmacological and genetic perturbation using in vitro cell models, in vivo xenografts, and ex vivo in patient-derived explants (PDE).Results: Key findings reveal: i) the first-in-field DNA-PK protein-protein interactome; ii) numerous DNA-PK novel partners involved in glycolysis, iii) DNA-PK interacts with, phosphorylates (in vitro) and increases the enzymatic activity of glycolytic enzymes ALDOA and PKM2, iv) DNA-PK drives synthesis of glucose-derived pyruvate and lactate, v) DNA-PK regulates glycolysis in vitro, in vivo and ex vivo, and vi) combination of DNA-PK inhibitor with glycolytic inhibitor 2-deoxyglucose leads to additive antiproliferative effects in aggressive disease.Conclusions: Findings herein unveil novel DNA-PK partners, substrates, and function in PCa. The role of DNA-PK impacts glycolysis through direct interaction with glycolytic enzymes and modulation of enzymatic activity. These events support energy production Research.

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“…Genomic instability resulting from mutations in DNA repair genes is a hallmark of most cancers and plays a central role in tumor initiation and progression [ 34 , 35 ]. Recent studies have revealed the close relationship between metabolic reprogramming and cancer genomic instability [ 36 ]. For instance, glycolysis was found to contribute to DNA metabolism by providing metabolites essential for the biosynthesis of nucleotides.…”

Section: Discussionmentioning

confidence: 99%

Alteration in glycolytic/cholesterogenic gene expression is associated with bladder cancer prognosis and immune cell infiltration

et al. 2022

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Background Oncogenic metabolic reprogramming contributes to tumor growth and immune evasion. The intertumoral metabolic heterogeneity and interaction of distinct metabolic pathways may determine patient outcomes. In this study, we aim to determine the clinical and immunological significance of metabolic subtypes according to the expression levels of genes related to glycolysis and cholesterol-synthesis in bladder cancer (BCa). Methods Based on the median expression levels of glycolytic and cholesterogenic genes, patients were stratified into 4 subtypes (mixed, cholesterogenic, glycolytic, and quiescent) in an integrated cohort including TCGA, GSE13507, and IMvigor210. Clinical, genomic, transcriptomic, and tumor microenvironment characteristics were compared between the 4 subtypes. Results The 4 metabolic subtypes exhibited distinct clinical, molecular, and genomic patterns. Compared to quiescent subtype, mixed subtype was more likely to be basal tumors and was significantly associated with poorer prognosis even after controlling for age, gender, histological grade, clinical stage, and molecular phenotypes. Additionally, mixed tumors harbored a higher frequency of RB1 and LRP1B copy number deletion compared to quiescent tumors (25.7% vs. 12.7 and 27.9% vs. 10.2%, respectively, both adjusted P value< 0.05). Furthermore, aberrant PIK3CA expression level was significantly correlated with those of glycolytic and cholesterogenic genes. The quiescent subtype was associated with lower stemness indices and lower signature scores for gene sets involved in genomic instability, including DNA replication, DNA damage repair, mismatch repair, and homologous recombination genes. Moreover, quiescent tumors exhibited lower expression levels of pyruvate dehydrogenase kinases 1-3 (PDK1-3) than the other subtypes. In addition, distinct immune cell infiltration patterns were observed across the 4 metabolic subtypes, with greater infiltration of M0/M2 macrophages observed in glycolytic and mixed subtypes. However, no significant difference in immunotherapy response was observed across the 4 metabolic subtypes. Conclusion This study proposed a new metabolic subtyping method for BCa based on genes involved in glycolysis and cholesterol synthesis pathways. Our findings may provide novel insight for the development of personalized subtype-specific treatment strategies targeting metabolic vulnerabilities.

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Cell Metabolism and DNA Repair Pathways: Implications for Cancer Therapy

Cited by 48 publications

References 127 publications

A novel pyroptosis-related lncRNA signature for prognostic prediction in patients with lung adenocarcinoma

A novel pyroptosis-related lncRNA signature for prognostic prediction in patients with lung adenocarcinoma

A Novel Role for DNA-PK in Metabolism by Regulating Glycolysis in Castration-Resistant Prostate Cancer

Alteration in glycolytic/cholesterogenic gene expression is associated with bladder cancer prognosis and immune cell infiltration

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