Therapeutic Targeting Hypoxia-Inducible Factor (HIF-1) in Cancer: Cutting Gordian Knot of Cancer Cell Metabolism

Sharma, Abhilasha; Sinha, Sonam; Shrivastava, Neeta

doi:10.3389/fgene.2022.849040

Cited by 57 publications

(35 citation statements)

References 95 publications

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“…For example, c-Myc activates the glycolytic pathway via upregulation of ALDO, ENO, Glc transporters (GluT), GAPDH, HK, PFK, PGI, TPI, PGK, PGAM and PK. In addition, c-Myc increases glutaminolysis level to generate NADPH and mitochondrial level via mitochondrial transcription factor, directing to anabolic metabolism [ 13 ]. Similarly, HIF also activates the glycolysis pathway by blocking of pyruvate to mitochondrial entrance.…”

Section: Carbohydrate Metabolic Reprogramming and Adaptation And Dire...mentioning

confidence: 99%

Revisited Metabolic Control and Reprogramming Cancers by Means of the Warburg Effect in Tumor Cells

Abekura

Kim

Chang

et al. 2022

IJMS

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Aerobic glycolysis is an emerging hallmark of many human cancers, as cancer cells are defined as a “metabolically abnormal system”. Carbohydrates are metabolically reprogrammed by its metabolizing and catabolizing enzymes in such abnormal cancer cells. Normal cells acquire their energy from oxidative phosphorylation, while cancer cells acquire their energy from oxidative glycolysis, known as the “Warburg effect”. Energy–metabolic differences are easily found in the growth, invasion, immune escape and anti-tumor drug resistance of cancer cells. The glycolysis pathway is carried out in multiple enzymatic steps and yields two pyruvate molecules from one glucose (Glc) molecule by orchestral reaction of enzymes. Uncontrolled glycolysis or abnormally activated glycolysis is easily observed in the metabolism of cancer cells with enhanced levels of glycolytic proteins and enzymatic activities. In the “Warburg effect”, tumor cells utilize energy supplied from lactic acid-based fermentative glycolysis operated by glycolysis-specific enzymes of hexokinase (HK), keto-HK-A, Glc-6-phosphate isomerase, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase, phosphofructokinase (PFK), phosphor-Glc isomerase (PGI), fructose-bisphosphate aldolase, phosphoglycerate (PG) kinase (PGK)1, triose phosphate isomerase, PG mutase (PGAM), glyceraldehyde-3-phosphate dehydrogenase, enolase, pyruvate kinase isozyme type M2 (PKM2), pyruvate dehydrogenase (PDH), PDH kinase and lactate dehydrogenase. They are related to glycolytic flux. The key enzymes involved in glycolysis are directly linked to oncogenesis and drug resistance. Among the metabolic enzymes, PKM2, PGK1, HK, keto-HK-A and nucleoside diphosphate kinase also have protein kinase activities. Because glycolysis-generated energy is not enough, the cancer cell-favored glycolysis to produce low ATP level seems to be non-efficient for cancer growth and self-protection. Thus, the Warburg effect is still an attractive phenomenon to understand the metabolic glycolysis favored in cancer. If the basic properties of the Warburg effect, including genetic mutations and signaling shifts are considered, anti-cancer therapeutic targets can be raised. Specific therapeutics targeting metabolic enzymes in aerobic glycolysis and hypoxic microenvironments have been developed to kill tumor cells. The present review deals with the tumor-specific Warburg effect with the revisited viewpoint of recent progress.

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Section: Carbohydrate Metabolic Reprogramming and Adaptation And Dire...mentioning

confidence: 99%

Revisited Metabolic Control and Reprogramming Cancers by Means of the Warburg Effect in Tumor Cells

Abekura

Kim

Chang

et al. 2022

IJMS

View full text Add to dashboard Cite

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“…This alteration leads to the activation of several compensative pathways that alter the physiological behavior of cancer cells and further modify the surrounding TME by the modification of cytokines and growth factors’ release. In particular, the activation of the hypoxia-induced factor (HIF) alters the cells’ death mechanisms and promotes the cancer cells’ survival by inhibiting apoptotic processes [ 43 ]. This factor is also strongly implicated in the tumor’s metabolic changes by inducing the overexpression of trans-membrane glucose transporters, exacerbating the Warburg effect and then promoting glycolysis instead of the oxidative phosphorylation of glucose [ 43 , 44 ].…”

Section: Role Of Tumor Microenvironment In Cancer Progressionmentioning

confidence: 99%

“…In particular, the activation of the hypoxia-induced factor (HIF) alters the cells’ death mechanisms and promotes the cancer cells’ survival by inhibiting apoptotic processes [ 43 ]. This factor is also strongly implicated in the tumor’s metabolic changes by inducing the overexpression of trans-membrane glucose transporters, exacerbating the Warburg effect and then promoting glycolysis instead of the oxidative phosphorylation of glucose [ 43 , 44 ]. This glucose metabolic alteration, in turn, leads to a large production of lactate which is accumulated in the extracellular microenvironment and leads to the tumor acidosis.…”

Section: Role Of Tumor Microenvironment In Cancer Progressionmentioning

confidence: 99%

Macrophage-Derived Extracellular Vesicles: A Promising Tool for Personalized Cancer Therapy

et al. 2022

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The incidence of cancer is increasing dramatically, affecting all ages of the population and reaching an ever higher worldwide mortality rate. The lack of therapies’ efficacy is due to several factors such as a delay in diagnosis, tumor regrowth after surgical resection and the occurrence of multidrug resistance (MDR). Tumor-associated immune cells and the tumor microenvironment (TME) deeply affect the tumor’s progression, leading to several physicochemical changes compared to physiological conditions. In this scenario, macrophages play a crucial role, participating both in tumor suppression or progression based on the polarization of onco-suppressive M1 or pro-oncogenic M2 phenotypes. Moreover, much evidence supports the pivotal role of macrophage-derived extracellular vesicles (EVs) as mediators in TME, because of their ability to shuttle the cell–cell and organ–cell communications, by delivering nucleic acids and proteins. EVs are lipid-based nanosystems with a broad size range distribution, which reflect a similar composition of native parent cells, thus providing a natural selectivity towards target sites. In this review, we discuss the impact of macrophage-derived EVs in the cancer’s fate as well as their potential implications for the development of personalized anticancer nanomedicine.

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“…Melanocytes in the dermo-epidermic zone live and develop in hypoxic conditions. The hypoxic microenvironment of the skin could favor the oncogenic transformation of melanocytes [ 11 , 12 ]. Hypoxia could influence cutaneous melanoma progression by evidence of a proliferative phenotype and invasive potential [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Hypoxia-Nitric Oxide Axis and the Associated Damage Molecular Pattern in Cutaneous Melanoma

Ene

Nicolae

2022

JPM

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Hypoxia was intensively studied in cancer during the last few decades, being considered a characteristic of the tumor microenvironment. The aim of the study was to evaluate the capacity of tumor cells to adapt to the stress generated by limited oxygen tissue in cutaneous melanoma. We developed a case–control prospective study that included 52 patients with cutaneous melanoma and 35 healthy subjects. We focused on identifying and monitoring hypoxia, the dynamic of nitric oxide (NO) serum metabolites and posttranslational metabolic disorders induced by NO signaling according to the clinical, biological and tumoral characteristics of the melanoma patients. Our study showed high levels of hypoxia-inducible factor-1a (HIF-1a) and hypoxia-inducible factor-2a (HIF-2a) in the melanoma patients. Hypoxia-inducible factors (HIFs) control the capacity of tumor cells to adapt to low levels of oxygen. Hypoxia regulated the nitric oxide synthase (NOS) expression and activity. In the cutaneous melanoma patients, disorders in NO metabolism were detected. The serum levels of the NO metabolites were significantly higher in the melanoma patients. NO signaling influenced the tumor microenvironment by modulating tumoral proliferation and sustaining immune suppression. Maintaining NO homeostasis in the hypoxic tumoral microenvironment could be considered a future therapeutic target in cutaneous melanoma.

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Therapeutic Targeting Hypoxia-Inducible Factor (HIF-1) in Cancer: Cutting Gordian Knot of Cancer Cell Metabolism

Cited by 57 publications

References 95 publications

Revisited Metabolic Control and Reprogramming Cancers by Means of the Warburg Effect in Tumor Cells

Revisited Metabolic Control and Reprogramming Cancers by Means of the Warburg Effect in Tumor Cells

Macrophage-Derived Extracellular Vesicles: A Promising Tool for Personalized Cancer Therapy

Hypoxia-Nitric Oxide Axis and the Associated Damage Molecular Pattern in Cutaneous Melanoma

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