From Warburg effect to Reverse Warburg effect; the new horizons of anti-cancer therapy

Benny, Sonu; Mishra, Rohan; Manojkumar, Maneesha K; Aneesh, T P

doi:10.1016/j.mehy.2020.110216

Cited by 61 publications

(51 citation statements)

References 59 publications

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“…In this context fits the theory of the reverse Warburg effect according to which the aerobic glycolysis in the cells of the tumor stroma would have the role of providing, in addition to ATP, metabolites for the generation of further ATP through OXPHOS in cancer cells. Moreover, the metabolic coupling between stromal and tumor cell, with the exchange of useful metabolites, would also allow the tumor cell to increase its proliferation and reduce cell death (Xu et al, 2015;Wilde et al, 2017;Benny et al, 2020).…”

Section: Cholesterol Homeostasis In Normal and Cancer Cellsmentioning

confidence: 99%

Role of Cholesterol and Lipid Rafts in Cancer Signaling: A Promising Therapeutic Opportunity?

Vona

Iessi

Matarrese

2021

Front. Cell Dev. Biol.

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Cholesterol is a lipid molecule that plays an essential role in a number of biological processes, both physiological and pathological. It is an essential structural constituent of cell membranes, and it is fundamental for biosynthesis, integrity, and functions of biological membranes, including membrane trafficking and signaling. Moreover, cholesterol is the major lipid component of lipid rafts, a sort of lipid-based structures that regulate the assembly and functioning of numerous cell signaling pathways, including those related to cancer, such as tumor cell growth, adhesion, migration, invasion, and apoptosis. Considering the importance of cholesterol metabolism, its homeostasis is strictly regulated at every stage: import, synthesis, export, metabolism, and storage. The alterations of this homeostatic balance are known to be associated with cardiovascular diseases and atherosclerosis, but mounting evidence also connects these behaviors to increased cancer risks. Although there is conflicting evidence on the role of cholesterol in cancer development, most of the studies consistently suggest that a dysregulation of cholesterol homeostasis could lead to cancer development. This review aims to discuss the current understanding of cholesterol homeostasis in normal and cancerous cells, summarizing key findings from recent preclinical and clinical studies that have investigated the role of major players in cholesterol regulation and the organization of lipid rafts, which could represent promising therapeutic targets.

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Section: Cholesterol Homeostasis In Normal and Cancer Cellsmentioning

confidence: 99%

Role of Cholesterol and Lipid Rafts in Cancer Signaling: A Promising Therapeutic Opportunity?

Vona

Iessi

Matarrese

2021

Front. Cell Dev. Biol.

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“…In the reverse Warburg effect hypothesis, transformed cells (preserved OXPHOS, anabolic, stem-like) and adjacent fibroblasts (glycolytic, catabolic) coexist [ [143] , [144] , [145] ], whereas in the mitochondrial theory of cancer, this cooperative link is not relevant for mitochondrially impaired cancer cells [ 146 ]. Autophagy, mitochondrial dynamics, and metabolic coupling have been described as possible contributors to tumor growth, but they have never been shown to produce sufficient ATP to sustain proliferation on their own [ 63 , 111 , 147 ].…”

Section: Metabolic Flexibility and Therapy In The Era Of Precision Medicinementioning

confidence: 99%

Metabolic therapy and bioenergetic analysis: The missing piece of the puzzle

Duraj

Carrión-Navarro

Seyfried

et al. 2021

Molecular Metabolism

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Background Aberrant metabolism is recognized as a hallmark of cancer, a pillar necessary for cellular proliferation. Regarding bioenergetics (ATP generation), most cancers display a preference not only toward aerobic glycolysis (“Warburg effect”) and glutaminolysis (mitochondrial substrate level-phosphorylation) but also toward other metabolites such as lactate, pyruvate, and fat-derived sources. These secondary metabolites can assist in proliferation but cannot fully cover ATP demands. Scope of review The concept of a static metabolic profile is challenged by instances of heterogeneity and flexibility to meet fuel/anaplerotic demands. Although metabolic therapies are a promising tool to improve therapeutic outcomes, either via pharmacological targets or press-pulse interventions, metabolic plasticity is rarely considered. Lack of bioenergetic analysis in vitro and patient-derived models is hindering translational potential. Here, we review the bioenergetics of cancer and propose a simple analysis of major metabolic pathways, encompassing both affordable and advanced techniques. A comprehensive compendium of Seahorse XF bioenergetic measurements is presented for the first time. Major conclusions Standardization of principal readouts might help researchers to collect a complete metabolic picture of cancer using the most appropriate methods depending on the sample of interest.

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“…In this case, one molecule of glucose is converted into 2 molecules of lactic acid and 2 H + to produce only 2 molecules of ATP. Thus, in normal cells, the balance between OXPHOS and glycolysis is determined by the amount of oxygen available [ 62 ].…”

Section: Warburg Effect and Glucose Metabolism Reprogrammingmentioning

confidence: 99%

“…Basing on this theory, hypoxic cancer cells induce the nearby CAFs to follow aerobic glycolysis and then to produce lactate that is released in the TME through MTC1–4 transporters. Lactate is then transferred back to oxygenated tumor cells (or oxygenated CAFs) where it is utilized by OXPHOS to produce further ATP and metabolites necessary for cancer cell survival [ 62 , 145 , 155 , 157 , 158 ]. The remaining lactate is stored in the extracellular TME contributing to acidification.…”

Section: Tumor Microenvironment and Cancer Cell Metabolismmentioning

confidence: 99%

“…The remaining lactate is stored in the extracellular TME contributing to acidification. The tight metabolical interplay between tumor cells and CAFs would support the metabolite exchange and provide cancer cells not only of ATP, but also of other molecules necessary for their proliferation and growth, and useful to limit cell death [ 62 , 153 , 159 ].…”

Section: Tumor Microenvironment and Cancer Cell Metabolismmentioning

confidence: 99%

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Targeting the Interplay between Cancer Metabolic Reprogramming and Cell Death Pathways as a Viable Therapeutic Path

et al. 2021

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In cancer cells, metabolic adaptations are often observed in terms of nutrient absorption, biosynthesis of macromolecules, and production of energy necessary to meet the needs of the tumor cell such as uncontrolled proliferation, dissemination, and acquisition of resistance to death processes induced by both unfavorable environmental conditions and therapeutic drugs. Many oncogenes and tumor suppressor genes have a significant effect on cellular metabolism, as there is a close relationship between the pathways activated by these genes and the various metabolic options. The metabolic adaptations observed in cancer cells not only promote their proliferation and invasion, but also their survival by inducing intrinsic and acquired resistance to various anticancer agents and to various forms of cell death, such as apoptosis, necroptosis, autophagy, and ferroptosis. In this review we analyze the main metabolic differences between cancer and non-cancer cells and how these can affect the various cell death pathways, effectively determining the susceptibility of cancer cells to therapy-induced death. Targeting the metabolic peculiarities of cancer could represent in the near future an innovative therapeutic strategy for the treatment of those tumors whose metabolic characteristics are known.

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From Warburg effect to Reverse Warburg effect; the new horizons of anti-cancer therapy

Cited by 61 publications

References 59 publications

Role of Cholesterol and Lipid Rafts in Cancer Signaling: A Promising Therapeutic Opportunity?

Role of Cholesterol and Lipid Rafts in Cancer Signaling: A Promising Therapeutic Opportunity?

Metabolic therapy and bioenergetic analysis: The missing piece of the puzzle

Targeting the Interplay between Cancer Metabolic Reprogramming and Cell Death Pathways as a Viable Therapeutic Path

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