Dysregulation of metabolic enzymes in tumor and stromal cells: Role in oncogenesis and therapeutic opportunities

Khan, Mohammad Aslam; Zubair, Haseeb; Anand, Shashi; Srivastava, Sanjeev K.; Singh, Seema; Singh, Ajay P.

doi:10.1016/j.canlet.2020.01.003

Cited by 37 publications

(24 citation statements)

References 109 publications

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“…Liu 9 BioMed Research International glioblastoma [45]. There are also some researches focusing on the relationship between glycolysis and tumor oncogenesis, development, proliferation, and invasion [47,48]. Most studies have focused on the relationship between glycolysis and tumor oncogenesis, development, proliferation, and invasion [49].…”

Section: Discussionmentioning

confidence: 99%

[Retracted] A Prognostic Model for Brain Glioma Patients Based on 9 Signature Glycolytic Genes

Xiao

et al. 2021

BioMed Research International

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Objective. To screen glycolytic genes linked to the glioma prognosis and construct the prognostic model. Methods. The relevant data of glioma were downloaded from TCGA and GTEx databases. GSEA of glycolysis-related pathways was carried out, and enriched differential genes were extracted. Screening out prognostic-related genes with conspicuous significance and construction of the prognostic model were conducted by multivariate Cox regression analysis and Lasso regression analysis. The model was evaluated, and cBioPortal was used to analyze the mutation of the model gene. The expression of the model gene in tumor and normal colon tissue was analyzed. The model was used to evaluate the prognosis of patients in different groups to verify the applicability of the model. Results. 339 differentially glycolytic-related genes were enriched in REACTOME_GLYCOLYSIS, GLYCOLYTIC_PROCESS, HALLMARK_GLYCOLYSIS, and other pathways. We obtained 9 key prognostic genes and constructed the prognostic evaluation model. The 3-year AUC values of the ROC curve display model are greater than 0.75, which indicates that the accuracy of the model is good. The relation of age and risk score to prognosis is shown by univariate and multivariate Cox analysis. The expression of SRD5A3, MDH2, and B3GAT3 genes was significantly upregulated in the tumor tissues, while the HDAC4 and G6PC2 genes were downregulated. The mutation rate of MDH2 and HDAC4 genes was the highest. This model could effectively distinguish the risk of poor prognosis of patients in any age stage. Conclusion. The prognostic assessment models based on glycolysis-related nine-gene signature could accurately predict the prognosis of patients with GBM.

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Section: Discussionmentioning

confidence: 99%

[Retracted] A Prognostic Model for Brain Glioma Patients Based on 9 Signature Glycolytic Genes

Xiao

et al. 2021

BioMed Research International

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“…Several key metabolic enzymes [pyruvate kinase M2 (PKM2), pyruvate dehydrogenase kinase 1 (PDK1) and hexokinase 2] have been found to play an important role in the Warburg effect (18)(19)(20). The changes in key enzymes can lead to an enhanced glycolytic ability, promote glucose uptake into tumor cells and increase the accumulation of lactic acid, thus further supporting tumor growth and development (21). 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB2) is an enzyme that regulates the synthesis and degradation of fructose-2,6-bisphosphate (Fru-2, 6-P2), which is widely expressed in a variety of cancer cells, such as ovarian, breast and pancreatic cancer cells (22,23).…”

Section: Introductionmentioning

confidence: 99%

Shikonin inhibits the Warburg effect, cell proliferation, invasion and migration by downregulating PFKFB2 expression in lung cancer

Sha

Liu

et al. 2021

Mol Med Rep

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Lung cancer is one of the most lethal diseases and therefore poses a significant threat to human health. The Warburg effect, which is the observation that cancer cells predominately produce energy through glycolysis, even under aerobic conditions, is a hallmark of cancer. 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2 (PFKFB) is an important regulator of glycolysis. Shikonin is a Traditional Chinese herbal medicine, which has been reported to exert antitumor effects. The present study aimed to investigate the anticancer activity of shikonin in lung cancer. Cell Counting Kit-8 (CCK-8) and colony formation assays were used to analyze proliferation in A549 and H446 cells. Wound healing and Transwell assays were used to measure migration and invasion in A549 and H446 cells. Cell apoptosis was analyzed using flow cytometry. Lactate levels, glucose uptake and cellular ATP levels were measured using their corresponding commercial kits. Western blotting was performed to analyze the protein expression levels of key enzymes involved in aerobic glucose metabolism. Reverse transcription-quantitative PCR was used to analyze the mRNA expression levels of PFKFB2. The results of the present study revealed that PFKFB2 expression levels were significantly upregulated in NSCLC tissues. Shikonin treatment decreased the proliferation, migration, invasion, glucose uptake, lactate levels, ATP levels and PFKFB2 expression levels and increased apoptosis in lung cancer cells in a dose-dependent manner. The overexpression of PFKFB2 increased the proliferation, migration, glucose uptake, lactate levels and ATP levels in lung cancer cells, while the knockdown of PFKFB2 expression exerted the opposite effects. Moreover, there were no significant differences in lung cancer cell migration, apoptosis, glucose uptake, lactate levels and ATP levels between cells with knocked down PFKFB2 expression or treated with shikonin and the knockdown of PFKFB2 in cells treated with shikonin. In conclusion, the results of the present study revealed that shikonin inhibited the Warburg effect and exerted antitumor activity in lung cancer cells, which was associated with the downregulation of PFKFB2 expression.

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“…In tumor tissues, dysregulation of extracellular (e.g., matrix metalloproteinase, proteinase, hyaluronidase) and intracellular (cathepsin B) enzymatic activity frequently occurs. [51] Since enzymes catalyze chemical reactions with high specificity and efficiency under mild conditions, utilizing enzymatic activity as a biological stimulus for controlled payload release can provide new strategies for the design of delivery systems. [52] Several digestive enzymes such as esterase, β-glucuronidase and lipase are highly expressed in lysosomes of nearly all eukaryotic cells.…”

Section: Enzymesmentioning

confidence: 99%

Bioinspired and Biomimetic Delivery Platforms for Cancer Vaccines

et al. 2021

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However, despite the recent success of ICB and CAR-T therapies in cancer clinical trials, these approaches still face limitations as only a small fraction of patients derive clinical benefit. [4] ICB therapy cannot prime the immune system to specifically recognize or target tumor cells. This approach only works on related inhibitory signaling pathways, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1), and exerts therapeutic efficacy when antigen-specific cytotoxic T lymphocytes (CTLs) are already present. [5] Successful treatment outcomes will therefore require the identification of predictive biomarkers to ascertain if the host tumor will respond to ICB therapeutics administered. [6] Although CAR-T has seen remarkable success in hematological malignancies, response rates of patients with solid tumors remain low. [7] Clinical applications of CAR-T therapies are limited due to on-target/off-tumor toxicities and the need for predefined tumor antigen (Ag). [8] Notwithstanding, the marked progress of immunotherapy using ICB and CAR-T has seen a surge of reinvigorated interest in cancer vaccine development. [9] Cancer vaccines involve the administration of tumor Ags and/or adjuvants to train the immune system to recognize and attack tumor cells. [10] Although vaccines against infectious diseases have been one of the greatest medical accomplishments of modern medicine, the application of vaccines in cancer treatment has seen far lesser success, and, till date only few cancer vaccines have received approval for clinical use. [11] Given their Cancer vaccines aim at eliciting tumor-specific responses for the immune system to identify and eradicate malignant tumor cells while sparing the normal tissues. Furthermore, cancer vaccines can potentially induce long-term immunological memory for antitumor responses, preventing metastasis and cancer recurrence, thus presenting an attractive treatment option in cancer immunotherapy. However, clinical efficacy of cancer vaccines has remained low due to longstanding challenges, such as poor immunogenicity, immunosuppressive tumor microenvironment, tumor heterogeneity, inappropriate immune tolerance, and systemic toxicity. Recently, bioinspired materials and biomimetic technologies have emerged to play a part in reshaping the field of cancer nanomedicine. By mimicking desirable chemical and biological properties in nature, bioinspired engineering of cancer vaccine delivery platforms can effectively transport therapeutic cargos to tumor sites, amplify antigen and adjuvant bioactivities, and enable spatiotemporal control and on-demand immunoactivation. As such, integration of biomimetic designs into delivery platforms for cancer vaccines can enhance efficacy while retaining good safety profiles, which contributes to expediting the clinical translation of cancer vaccines. Recent advances in bioinspired delivery platforms for cancer vaccines, existing obstacles faced, as well as insights and future directions for the field are discu...

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Dysregulation of metabolic enzymes in tumor and stromal cells: Role in oncogenesis and therapeutic opportunities

Cited by 37 publications

References 109 publications

[Retracted] A Prognostic Model for Brain Glioma Patients Based on 9 Signature Glycolytic Genes

[Retracted] A Prognostic Model for Brain Glioma Patients Based on 9 Signature Glycolytic Genes

Shikonin inhibits the Warburg effect, cell proliferation, invasion and migration by downregulating PFKFB2 expression in lung cancer

Bioinspired and Biomimetic Delivery Platforms for Cancer Vaccines

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