IRF7 inhibits the Warburg effect via transcriptional suppression of PKM2 in osteosarcoma

Introduction: GBMs are resistant to apoptosis induced by the hypoxic microenvironment and standard therapies including radiation and chemotherapy. We postulate that the Warburg effect, a preferential glycolytic phenotype of tumor cells even under aerobic conditions, plays a role in these aberrant pro-survival signals. In this study we quantitatively examined the expression profile of hypoxia-related glycolytic genes within pathologically- and MRI-defined “centre” and “periphery” of GBMs. We hypothesize that expression of hypoxia-induced glycolytic genes, particularly hexokinase 2 (HK2), favours cell survival and modulates resistance to tumour cell apoptosis by inhibiting the intrinsic mitochondrial apoptotic pathway. Methods: GBM patients underwent conventional T1-weighted contrast-enhanced MRI and MR spectroscopy studies on a 3.0T GE scanner, prior to stereotactic sampling (formalin and frozen) from regions which were T1-Gad enhancing (“centre”) and T2-positive, T1-Gad negative (“periphery”). Real-time qRT-PCR was performed to quantify regional gene expression of glycolytic genes including HK2. In vitro functional studies were performed in U87 and U373 GBM cell lines grown in normoxic (21% pO2) and hypoxic (< 1%pO2) conditions, transfected with HK2 siRNA followed by measurement of cell proliferation (BrdU), apoptosis (activated caspase 3/7, TUNEL, cytochrome c release) and viability (MTS assay). Results: There exists a differential expression profile of glycolytic enzymes between the hypoxic center and relatively normoxic periphery of GBMs. Under hypoxic conditions, there is increased expression of HK2 at the mitochondrial membrane in GBM cells. In vitro HK2 knockdown led to decreased cell survival and increased apoptosis via the intrinsic mitochondrial pathway, as seen by increased mitochondrial release of cytochrome-C. Conclusions: Increased expression of HK2 in the centre of GBMs promotes cell survival and confers resistance to apoptosis, as confirmed by in vitro studies. In vivo intracranial xenograft studies with injection of HK2-shRNA are currently being performed. HK2 and possibly other glycolytic enzymes may provide a target for enhanced therapeutic responsiveness thereby improving prognosis of patients with GBMs.

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Faculty Opinions recommendation of AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717969930.793502989 ◽

2015 ◽

Author(s):

David Potter

Keyword(s):

Tumor Growth ◽

Warburg Effect ◽

Negative Regulator ◽

The Warburg Effect

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Faculty Opinions recommendation of A role for the mitochondrial pyruvate carrier as a repressor of the Warburg effect and colon cancer cell growth.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725254231.793505009 ◽

2015 ◽

Author(s):

Aurelio Teleman

Keyword(s):

Colon Cancer ◽

Cell Growth ◽

Cancer Cell ◽

Warburg Effect ◽

Colon Cancer Cell ◽

Cancer Cell Growth ◽

Mitochondrial Pyruvate Carrier ◽

The Warburg Effect

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Phytometabolites Targeting the Warburg Effect in Cancer Cells: A Mechanistic Review

Current Drug Targets ◽

10.2174/1389450117666160401124842 ◽

2017 ◽

Vol 18 (9) ◽

Cited By ~ 21

Author(s):

Mohadeseh Hasanpourghadi ◽

Chung Yeng Looi ◽

Ashok Kumar Pandurangan ◽

Gautam Sethi ◽

Won Fen Wong ◽

...

Keyword(s):

Cancer Cells ◽

Warburg Effect ◽

The Warburg Effect

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Metabolic reprogramming for cancer cells and their microenvironment: Beyond the Warburg Effect

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer ◽

10.1016/j.bbcan.2018.06.005 ◽

2018 ◽

Vol 1870 (1) ◽

pp. 51-66 ◽

Cited By ~ 44

Author(s):

Linchong Sun ◽

Caixia Suo ◽

Shi-ting Li ◽

Huafeng Zhang ◽

Ping Gao

Keyword(s):

Cancer Cells ◽

Warburg Effect ◽

Metabolic Reprogramming ◽

The Warburg Effect

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Refractory Hyperlactatemia and Hypoglycemia in an Adult with Non-Hodgkin’s Lymphoma: A Case Report and Review of the Warburg Effect

Case Reports in Oncology ◽

10.1159/000517658 ◽

2021 ◽

pp. 1159-1167

Author(s):

Zainab Al Maqrashi ◽

Mary Sedarous ◽

Avinash Pandey ◽

Catherine Ross ◽

Ahraaz Wyne

Keyword(s):

Lactic Acidosis ◽

Warburg Effect ◽

Hodgkin’S Lymphoma ◽

Abdominal Mass ◽

Hodgkin's Lymphoma ◽

Type B ◽

Elderly Male ◽

Non Hodgkin’S Lymphoma ◽

Non Hodgkin's Lymphoma ◽

The Warburg Effect

Lactate is a byproduct of anaerobic glycolysis, and hyperlactatemia is commonly seen in critically ill patients. We report a case of an elderly male presenting with undifferentiated constitutional symptoms, anemia, thrombocytopenia, severe lactic acidosis, refractory hypoglycemia, and a newly detected abdominal mass. A dedicated workup ruled out infectious etiologies and revealed metastatic non-Hodgkin’s lymphoma. This study explores etiologies of type B lactic acidosis in oncology patients, with a focus on Warburg’s effect, and its potential for prognostication.

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Heart failure—emerging roles for the mitochondrial pyruvate carrier

Cell Death and Differentiation ◽

10.1038/s41418-020-00729-0 ◽

2021 ◽

Author(s):

Mariana Fernandez-Caggiano ◽

Philip Eaton

Keyword(s):

Heart Failure ◽

Warburg Effect ◽

Translational Regulation ◽

Hypertrophic Growth ◽

Metabolic Adaptations ◽

Mitochondrial Pyruvate Carrier ◽

Heart Failure Progression ◽

Mitochondrial Oxidation ◽

Human And Mouse ◽

The Warburg Effect

AbstractThe mitochondrial pyruvate carrier (MPC) is the entry point for the glycolytic end-product pyruvate to the mitochondria. MPC activity, which is controlled by its abundance and post-translational regulation, determines whether pyruvate is oxidised in the mitochondria or metabolised in the cytosol. MPC serves as a crucial metabolic branch point that determines the fate of pyruvate in the cell, enabling metabolic adaptations during health, such as exercise, or as a result of disease. Decreased MPC expression in several cancers limits the mitochondrial oxidation of pyruvate and contributes to lactate accumulation in the cytosol, highlighting its role as a contributing, causal mediator of the Warburg effect. Pyruvate is handled similarly in the failing heart where a large proportion of it is reduced to lactate in the cytosol instead of being fully oxidised in the mitochondria. Several recent studies have found that the MPC abundance was also reduced in failing human and mouse hearts that were characterised by maladaptive hypertrophic growth, emulating the anabolic scenario observed in some cancer cells. In this review we discuss the evidence implicating the MPC as an important, perhaps causal, mediator of heart failure progression.

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Valproic acid Suppresses Breast Cancer Cell Growth Through Triggering Pyruvate Kinase M2 Isoform Mediated Warburg Effect

Cell Transplantation ◽

10.1177/09636897211027524 ◽

2021 ◽

Vol 30 ◽

pp. 096368972110275

Author(s):

Zhen Li ◽

Lina Yang ◽

Shuai Zhang ◽

Jiaqi Song ◽

Huanran Sun ◽

...

Keyword(s):

Breast Cancer ◽

Valproic Acid ◽

Cancer Therapy ◽

Pyruvate Kinase ◽

Histone Deacetylases ◽

Warburg Effect ◽

Broad Class ◽

Pyruvate Kinase M2 ◽

Breast Cancer Cell Growth ◽

The Warburg Effect

Energy metabolism programming is a hallmark of cancer, and serves as a potent target of cancer therapy. Valproic acid (VPA), a broad Class I histone deacetylases (HDACs) inhibitor, has been used as a therapeutic agent for cancer. However, the detail mechanism about the potential role of VPA on the Warburg effect in breast cancer remains unclear. In this study, we highlight that VPA significantly attenuates the Warburg effect by decreasing the expression of pyruvate kinase M2 isoform (PKM2), leading to inhibited cell proliferation and reduced colony formation in breast cancer MCF-7 and MDA-MB-231 cells. Mechanistically, Warburg effect suppression triggered by VPA was mediated by inactivation of ERK1/2 phosphorylation through reduced HDAC1 expression, resulting in suppressing breast cancer growth. In summary, we uncover a novel mechanism of VPA in regulating the Warburg effect which is essential for developing the effective approach in breast cancer therapy.

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BAI1 acts as a tumor suppressor in lung cancer A549 cells by inducing metabolic reprogramming via the SCD1/HMGCR module

Carcinogenesis ◽

10.1093/carcin/bgaa036 ◽

2020 ◽

Author(s):

Lei Liu ◽

Li Chai ◽

Jingjing Ran ◽

Ying Yang ◽

Li Zhang

Keyword(s):

Lung Cancer ◽

Tumor Suppressor ◽

Colony Formation ◽

Warburg Effect ◽

Poor Prognosis ◽

A549 Cells ◽

Angiogenesis Inhibitor ◽

Metabolic Reprogramming ◽

The Warburg Effect

Abstract Brain-specific angiogenesis inhibitor 1 (BAI1) is an important tumor suppressor in multiple cancers. However, the mechanisms behind its anti-tumor activity, particularly the relationship between BAI1 and metabolic aberrant of a tumor, remained unveiled. This study aimed to investigate whether BAI1 could inhibit biological functions in lung cancer A549 cells and the critical regulating molecules that induce metabolic reprogramming. Immunohistochemistry staining was performed to analyze whether variations in the expression of BAI1 in tumor tissues contributes to poor prognosis of lung cancer. Overexpressed BAI1 (BAI1-OE-A549) and control (Vector-NC-A549) were generated by lentiviral transfection. Biological function assays (proliferation, apoptosis, colony formation, invasion and in vivo metastasis), as well as metabolic reprogramming (by the Warburg effect and the glycolytic rate), were performed in both groups. Our results indicated that lower levels of BAI1 contributed to poor prognosis of lung cancer patients. Furthermore, overexpressed of BAI1 dramatically inhibited proliferation, migration, invasion, colony formation and in vivo metastasis of A549 cells. The Warburg effect and the Seahorse assay revealed that BAI1-OE induced metabolism reprogramming by inhibiting the Warburg effect and glycolysis. Further exploration indicated that BAI1 induced metabolic reprogramming by upregulating stearoyl-CoA desaturase 1 (SCD1) and inhibited 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR). Our study revealed a novel mechanism through which BAI1 acted as tumor suppressor by inducing metabolic reprogramming via the SCD1 and HMGCR module.

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