Dataset Information

The Reverse Warburg Effect is Associated with Fbp2-Dependent Hif1? Regulation in Cancer Cells Stimulated by Fibroblasts.

ABSTRACT: Fibroblasts are important contributors to cancer development. They create a tumor microenvironment and modulate our metabolism and treatment resistance. In the present paper, we demonstrate that healthy fibroblasts induce metabolic coupling with non-small cell lung cancer cells by down-regulating the expression of glycolytic enzymes in cancer cells and increasing the fibroblasts' ability to release lactate and thus support cancer cells with energy-rich glucose-derived metabolites, such as lactate and pyruvate-a process known as the reverse Warburg effect. We demonstrate that these changes result from a fibroblasts-stimulated increase in the expression of fructose bisphosphatase (Fbp) in cancer cells and the consequent modulation of Hif1? function. We show that, in contrast to current beliefs, in lung cancer cells, the predominant and strong interaction with the Hif1? form of Fbp is not the liver (Fbp1) but in the muscle (Fbp2) isoform. Since Fbp2 oligomerization state and thus, its role is regulated by AMP and NAD+-crucial indicators of cellular metabolic conditions-we hypothesize that the Hif1?-dependent regulation of the metabolism in cancer is modulated through Fbp2, a sensor of the energy and redox state of a cell.

SUBMITTER: Duda P

PROVIDER: S-EPMC7016812 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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The Reverse Warburg Effect is Associated with Fbp2-Dependent Hif1α Regulation in Cancer Cells Stimulated by Fibroblasts.

Duda Przemysław P Janczara Jakub J McCubrey James A JA Gizak Agnieszka A Rakus Dariusz D Rakus Dariusz D

Cells 20200114 1

Fibroblasts are important contributors to cancer development. They create a tumor microenvironment and modulate our metabolism and treatment resistance. In the present paper, we demonstrate that healthy fibroblasts induce metabolic coupling with non-small cell lung cancer cells by down-regulating the expression of glycolytic enzymes in cancer cells and increasing the fibroblasts' ability to release lactate and thus support cancer cells with energy-rich glucose-derived metabolites, such as lactat ...[more]

PMID: 31947613

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Project description:Cancer metabolism has received renewed interest as a potential target for cancer therapy. In this study, we use a multi-scale modeling approach to interrogate the implications of three metabolic scenarios of potential clinical relevance: the Warburg effect, the reverse Warburg effect and glutamine addiction. At the intracellular level, we construct a network of central metabolism and perform flux balance analysis (FBA) to estimate metabolic fluxes; at the cellular level, we exploit this metabolic network to calculate parameters for a coarse-grained description of cellular growth kinetics; and at the multicellular level, we incorporate these kinetic schemes into the cellular automata of an agent-based model (ABM), iDynoMiCS. This ABM evaluates the reaction-diffusion of the metabolites, cellular division and motion over a simulation domain. Our multi-scale simulations suggest that the Warburg effect provides a growth advantage to the tumor cells under resource limitation. However, we identify a non-monotonic dependence of growth rate on the strength of glycolytic pathway. On the other hand, the reverse Warburg scenario provides an initial growth advantage in tumors that originate deeper in the tissue. The metabolic profile of stromal cells considered in this scenario allows more oxygen to reach the tumor cells in the deeper tissue and thus promotes tumor growth at earlier stages. Lastly, we suggest that glutamine addiction does not confer a selective advantage to tumor growth with glutamine acting as a carbon source in the tricarboxylic acid (TCA) cycle, any advantage of glutamine uptake must come through other pathways not included in our model (e.g., as a nitrogen donor). Our analysis illustrates the importance of accounting explicitly for spatial and temporal evolution of tumor microenvironment in the interpretation of metabolic scenarios and hence provides a basis for further studies, including evaluation of specific therapeutic strategies that target metabolism.

Dataset Information

The Reverse Warburg Effect is Associated with Fbp2-Dependent Hif1? Regulation in Cancer Cells Stimulated by Fibroblasts.

Publications

The Reverse Warburg Effect is Associated with Fbp2-Dependent Hif1α Regulation in Cancer Cells Stimulated by Fibroblasts.

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