Genetic alterations in Krebs cycle and its impact on cancer pathogenesis

Sajnani, Karishma; Islam, Farhadul; Smith, Robert A.; Gopalan, Vinod; Lam, Alfred King-Yin

doi:10.1016/j.biochi.2017.02.008

Cited by 90 publications

(82 citation statements)

References 109 publications

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“…Krebs cycle is considered as central track for cellular oxidative metabolism and particularly crucial for the cancer cells which require constant supply of energy for the synthesis of proteins, lipids, and nucleic acids . Genetic defects in genes encoding for enzymes of TCA cycle such as isocitrate dehydrogenase, succinate dehydrogenase, and fumarate hydratase are associated with occurrence of cancer.…”

Section: Introductionmentioning

confidence: 99%

Malic enzyme 2 as a potential therapeutic drug target for cancer

et al. 2018

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Reprogrammed metabolic profile is a biochemical fingerprint of cancerous cells, which represents one of the "hallmarks of cancer." The aberrant expression pattern of enzymatic machineries orchestrates metabolic activities into a platform that ultimately promotes cellular growth, survival, and proliferation. The NADP(+)-dependent mitochondrial malic enzyme 2 (ME2) has been widely appreciated due to its function as a provider of pyruvate and reducing power to the cell for biosynthesis of fatty acids and nucleotides along with maintenance of redox balance. Multiple lines of evidences have indicated that ME2 is a bonafide therapeutic target and novel biomarker which plays critical role during tumorigenesis. The objective of this review is to provide an update on the cancer-specific role of ME2 in order to explore its potential for therapeutic opportunities. Furthermore, we have discussed the potential of genetic and pharmacological inhibitors of ME2 in the light of previous research work for therapeutic advancements in cancer treatment. It is contemplated that additional investigations should focus on the use of ME2 inhibitors in combinational therapies as rational combinations of metabolic inhibitors and chemotherapy may have the ability to cure cancer. © 2018 IUBMB Life, 70(11):1076-1083, 2018.

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Section: Introductionmentioning

confidence: 99%

Malic enzyme 2 as a potential therapeutic drug target for cancer

et al. 2018

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“…Early studies suggested that cancer cells bypass the TCA cycle and use aerobic glycolysis, but emerging evidence suggests that some cancer cells, particularly those with maladjusted expression of oncogenes and tumor suppressors, rely heavily on the TCA cycle to produce energy and synthesize large molecules (30). In a variety of cancers, including HCC, the expression or activity levels of the TCA cycle and related enzymes are generally dysregulated, which is a pivotal driver of cancer development and progression (31,32). In addition, wild-type P53 alos has an important effect on metabolism,the mutation of P53 will lead to the enhancement of glycolysis and the reduction of oxidative phosphorylation in tumor cells.…”

Section: Discussionmentioning

confidence: 99%

Increased E2F2 predicts poor prognosis in patients with HCC based on TCGA data

Zeng

Cao

Tang³

2020

Preprint

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Background E2F transcription factor 2(E2F2) plays an important role in the development and progression of various tumors, but its association with hepatocellular carcinoma remains unknown.The aim of our study was to investigate the role and clinical significance of E2F2 in hepatocellular carcinoma (HCC). Methods HCC raw data were extracted from TCGA. Wilcoxon signed-rank test, Kruskal-Wallis test and logistic regression was applied to analyze the the relationship between the expression of E2F2 and clinicalpathologic charateristics. Cox regression and Kaplan-Meier was employed to evaluate the correlation between clinicopathologic features and survial. The biological function of E2F2 was annotated by Gene set enrichment analysis (GSEA). Results The expression of E2F2 was increased in HCC samples. The expression of elevated E2F2 in HCC samples was prominentlly correlated with tumor grade (OR =2.62 for G3-4 vs. G1-2, p=1.80E-05), tumor stage (OR =1.74 for III-IV vs. I-II, p=0.03), topography (OR =1.64 for T3-4 vs.T1-2, p=0.04), tumor status (OR =1.88 for with tumor vs. tumor free, p= 3.79E-03), plasma AFP value (OR =3.18 for AFP≥400 vs AFP<20, p= 2.16E-04; OR=2.50 for 20≤AFP<400 vs AFP<20, p=2.56E-03). Increased E2F2 had a unfavorable OS (p=7.468e−05), PFI (p=3.183e−05), DFI (p=0.001), DSS (p=4.172e−05). Elevated E2F2 was independently bound up with OS (p = 4.4E-04, HR = 2.4 (95% CI [1.5-3.8])) and DSS (p = 7.6E-04, HR = 3.0, (95% CI [1.6-5.6])). GSEA disclosed that cell circle, RNA degradation, pyrimidine metabolism, base excision repair, aminoacyl tRNA biosynthesis, DNA replication, p53 signalling pathway, nucleotide excision repair, ubiquitin mediated proteolysis, citrate cycle TCA cycle were notably enriched in E2F2 high expression phenotype. Conclusions Elevated E2F2 can be a promissing independent prognostic biomarker and therapeutic target for HCC. Additionally, cell cycle, pyrimidine metabolism, DNA replication, p53 signalling pathway, ubiquitin mediated proteolysis, the citrate cycle TCA cycle may be the key pathway by which E2F2 participate in the initial and progression of HCC.

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“…Early studies suggested that cancer cells bypass the TCA cycle and use aerobic glycolysis, but emerging evidence suggests that some cancer cells, particularly those with maladjusted expression of oncogenes and tumor suppressors, rely heavily on the TCA cycle to produce energy and synthesize large molecules [35]. In a variety of cancers, including HCC, the expression or activity levels of the TCA cycle and related enzymes are generally dysregulated, which is a pivotal driver of cancer development and progression [36,37]. In addition, wild-type P53 also has an important effect on metabolism, the mutation of P53 will lead to the enhancement of glycolysis and the reduction of oxidative phosphorylation in tumor cells.…”

Section: Discussionmentioning

confidence: 99%

Increased E2F2 predicts poor prognosis in patients with HCC based on TCGA data

Zeng

Cao

Tang³

2020

Preprint

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Background: The E2F family of transcription factor 2 (E2F2) plays an important role in the development and progression of various tumors, but its association with hepatocellular carcinoma remains unknown. The aim of our study was to investigate the role and clinical significance of E2F2 in hepatocellular carcinoma (HCC).Methods: HCC raw data were extracted from The Cancer Genome Atlas (TCGA). Wilcoxon signed-rank test, Kruskal-Wallis test and logistic regression was applied to analyze the relationship between the expression of E2F2 and clinicopathologic characteristics. Cox regression and Kaplan-Meier was employed to evaluate the correlation between clinicopathologic features and survival. The biological function of E2F2 was annotated by Gene set enrichment analysis (GSEA).Results: The expression of E2F2 was increased in HCC samples. The expression of elevated E2F2 in HCC samples was prominently correlated with histologic grade (OR =2.62 for G3-4 vs. G1-2, p=1.80E-05), clinical stage (OR =1.74 for III-IV vs. I-II, p=0.03), T (OR =1.64 for T3-4 vs.T1-2, p=0.04), tumor status (OR =1.88 for with tumor vs. tumor free, p= 3.79E-03), plasma alpha fetoprotein (AFP) value (OR =3.18 for AFP≥400 vs AFP＜20, p= 2.16E-04; OR=2.50 for 20≤AFP＜400 vs AFP＜20, p=2.56E-03). Increased E2F2 had an unfavorable OS (p=7.468e−05), PFI (p=3.183e−05), DFI (p=0.001), DSS (p=4.172e−05). Elevated E2F2 was independently bound up with OS (p =0.004 , hazard ratio [HR]= 2.4 (95% CI [1.3-4.2])), DFI (P =0.029, hazard ratio [HR] = 2.0 (95% CI [1.1-3.7])) and PFI (P =0.005, hazard ratio [HR] = 2.2 (95% CI [1.3-3.9])) . GSEA disclosed that cell circle, RNA degradation, pyrimidine metabolism, base excision repair, aminoacyl tRNA biosynthesis, DNA replication, p53 signaling pathway, nucleotide excision repair, ubiquitin mediated proteolysis, citrate cycle TCA cycle were notably enriched in E2F2 high expression phenotype.Conclusions: Elevated E2F2 can be a promising independent prognostic biomarker and therapeutic target for HCC. Additionally, cell cycle, pyrimidine metabolism, DNA replication, p53 signaling pathway, ubiquitin mediated proteolysis, the citrate cycle TCA cycle may be the key pathway by which E2F2 participate in the initial and progression of HCC.

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Genetic alterations in Krebs cycle and its impact on cancer pathogenesis

Cited by 90 publications

References 109 publications

Malic enzyme 2 as a potential therapeutic drug target for cancer

Malic enzyme 2 as a potential therapeutic drug target for cancer

Increased E2F2 predicts poor prognosis in patients with HCC based on TCGA data

Increased E2F2 predicts poor prognosis in patients with HCC based on TCGA data

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