Crucial players in glycolysis: Cancer progress

Abbaszadeh, Zaka; Çeşmeli, Selin; Avcı, Çığır Biray

doi:10.1016/j.gene.2019.144158

Cited by 175 publications

(116 citation statements)

References 24 publications

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“…The metabolism of tumor cells is more active than the normal cells, thus tumor cells need more energy to keep their higher proliferation. 16 Glycolysis and oxidative phosphorylation are the two important metabolic pathways related to energy supply. Glycolysis is a relatively low-energy-providing pathway compared with oxidative phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

A glycolysis-based three-gene signature predicts survival in patients with lung squamous cell carcinoma

Huang

Zhang

Gong

et al. 2020

Preprint

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Background: Lung cancer is one of the most lethal and most prevalent malignant tumors worldwide, and lung squamous cell carcinoma (LUSC) is one of major histological subtypes. Although, numerous biomarkers were found to be associated with prognosis in LUSC, the prediction effect of a single gene biomarker is not sufficient, especially for glycolysis-related genes. Therefore, we aimed to develop a novel glycolysis-related gene signature to predict survival of patients with LUSC.Methods: The mRNA expression files and clinical information of LUSC were obtained from The Cancer Genome Atlas (TCGA) dataset.Results: Based on Gene set enrichment analysis (GSEA), we found 5 glycolysis-related gene sets were significantly enriched in LUSC tissues. Univariate and multivariate Cox proportional regression models were conducted to choose prognostic-related gene signature. Based on Cox proportional regression model, a risk score of three-gene signature (including HKDC1, ALDH7A1, and MDH1) was established to divide patients into high-risk and low-risk subgroups. We found that a risk score of three-gene signature was an independent of prognostic indicator in LUSC using multivariate Cox regression analysis. Additionally, based on the cBioPortal database, the rate of alterations in HKDC1, ALDH7A1, and MDH1 genes were 1.9%, 1.1%, and 5% in LUSC patients, respectively. Conclusion: In conclusion, a glycolysis-based three-gene signature could serve as a novel biomarker in predicting prognosis of patients with LUSC, which provided more gene targets to cure LUSC patients.

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Section: Discussionmentioning

confidence: 99%

A glycolysis-based three-gene signature predicts survival in patients with lung squamous cell carcinoma

Huang

Zhang

Gong

et al. 2020

Preprint

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“…First, ATP production in cancer cells is less dependent on the mitochondria than it is in normal cells. This difference means that cancer cells already have high ROS levels so they need to prevent further ROS generation in the mitochondria [92,93]. Second, cancer cell proliferation occurs faster than angiogenesis in the surrounding environment; therefore, cancer cells must adapt to a shortage of O 2 [94,95].…”

Section: Metabolic Shifts In Cancer: Glycolysis and Oxidative Phosphomentioning

confidence: 99%

Insights into the New Cancer Therapy through Redox Homeostasis and Metabolic Shifts

Hyun

2020

Cancers

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Modest levels of reactive oxygen species (ROS) are necessary for intracellular signaling, cell division, and enzyme activation. These ROS are later eliminated by the body’s antioxidant defense system. High amounts of ROS cause carcinogenesis by altering the signaling pathways associated with metabolism, proliferation, metastasis, and cell survival. Cancer cells exhibit enhanced ATP production and high ROS levels, which allow them to maintain elevated proliferation through metabolic reprograming. In order to prevent further ROS generation, cancer cells rely on more glycolysis to produce ATP and on the pentose phosphate pathway to provide NADPH. Pro-oxidant therapy can induce more ROS generation beyond the physiologic thresholds in cancer cells. Alternatively, antioxidant therapy can protect normal cells by activating cell survival signaling cascades, such as the nuclear factor erythroid 2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) pathway, in response to radio- and chemotherapeutic drugs. Nrf2 is a key regulator that protects cells from oxidative stress. Under normal conditions, Nrf2 is tightly bound to Keap1 and is ubiquitinated and degraded by the proteasome. However, under oxidative stress, or when treated with Nrf2 activators, Nrf2 is liberated from the Nrf2-Keap1 complex, translocated into the nucleus, and bound to the antioxidant response element in association with other factors. This cascade results in the expression of detoxifying enzymes, including NADH-quinone oxidoreductase 1 (NQO1) and heme oxygenase 1. NQO1 and cytochrome b5 reductase can neutralize ROS in the plasma membrane and induce a high NAD+/NADH ratio, which then activates SIRT1 and mitochondrial bioenergetics. NQO1 can also stabilize the tumor suppressor p53. Given their roles in cancer pathogenesis, redox homeostasis and the metabolic shift from glycolysis to oxidative phosphorylation (through activation of Nrf2 and NQO1) seem to be good targets for cancer therapy. Therefore, Nrf2 modulation and NQO1 stimulation could be important therapeutic targets for cancer prevention and treatment.

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“…30 Overexpression of glycolytic enzymes, including GLUT1, HK-2, and PKM2, was related to the dysfunction of aerobic glycolysis. 31 Notably, aerobic glycolysis provides a large number of intermediates for macromolecular biosynthesis in cancer cells. Moreover, the acidic microenvironment, which was caused by the accumulation of lactate in tumor tissues contributes to metastasis and anti-cancer therapy resistance.…”

Section: Discussionmentioning

confidence: 99%

<p>Sinomenine Inhibits Non-Small Cell Lung Cancer via Downregulation of Hexokinases II-Mediated Aerobic Glycolysis</p>

Liu¹,

Yu²,

Zhou³

et al. 2020

OTT

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These authors contributed equally to this workBackground: Addiction to aerobic glycolysis is a common metabolic phenotype in human non-small cell lung cancer (NSCLC). The natural product Sinomenine (Sin) exhibits significant anti-tumor effects in various human cancers. However, the underlying mechanism remains elusive. Methods: The inhibitory effect of Sin on NSCLC cells was determined by MTS and soft agar assays. The glycolysis efficacy of NSCLC cells was examined by glucose uptake and lactate production. The activation of Akt signaling and the protein level of hexokinases II (HK2) were examined by immunoblot (IB), qRT-PCR, and immunohistochemical staining (IHC). The in vivo anti-tumor effect of Sin was validated by the xenograft mouse model. Results: We showed that HK2 is highly expressed in NSCLC tissues and cell lines. Depletion of HK2 suppressed cell viability, anchorage-independent colony formation, and xenograft tumor growth. Sinomenine exhibited a profound inhibitory effect on NSCLC cells by reducing HK2-mediated glycolysis both in vitro and in vivo. Ectopic overexpression of HK2 compromised these anti-tumor efficacies in sinomenine-treated NSCLC cells. Moreover, we revealed that sinomenine decreased Akt activity, which caused the downregulation of HK2-mediated glycolysis. Knockdown of Akt reduced HK2 protein level and impaired glycolysis. In contrast, overexpression of constitutively activated Akt1 reversed this phenotype. Conclusion: This study suggests that targeting HK2-mediated aerobic glycolysis is required for sinomenine-mediated anti-tumor activity.

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Crucial players in glycolysis: Cancer progress

Cited by 175 publications

References 24 publications

A glycolysis-based three-gene signature predicts survival in patients with lung squamous cell carcinoma

A glycolysis-based three-gene signature predicts survival in patients with lung squamous cell carcinoma

Insights into the New Cancer Therapy through Redox Homeostasis and Metabolic Shifts

<p>Sinomenine Inhibits Non-Small Cell Lung Cancer via Downregulation of Hexokinases II-Mediated Aerobic Glycolysis</p>

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