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  • Review Article
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Disrupting proton dynamics and energy metabolism for cancer therapy

Nature Reviews Cancer volume 13, pages 611–623 (2013)Cite this article

Subjects

Key Points

  • In rapidly growing cancer cells, oncogenes and hypoxia stimulate glycolytic metabolism, which generates increased amounts of lactic and carbonic acids.

  • Several pH-regulating systems — Na+/H+ exchangers (NHEs), carbonic anhydrases (CAIX and CAXII), HCO3− transporters, lactate/H+ symporters (monocarboxylate transporter 1 (MCT1) and MCT4) and intracellular H+ pumps — are essential to maintain a permissive intracellular pH (pHi) to optimize bioenergetic metabolism, cell cycle progression, growth and survival.

  • Cells lacking pH-regulating capabilities can enter growth arrest or can be 'killed' by H+. Targeting pH-regulating proteins in isolation (NHE1, CAs, MCTs and H+ pumps) impairs tumour progression.

  • Targeting the export of lactic acid from tumour cells (by disrupting MCTs) reduces glycolysis and growth rates, thus sensitizing tumour cells to treatment with mitochondrial complex I inhibitors (such as metformin and phenformin).

  • We propose the development of an acute 'metabolic knife' treatment that combines targeting of pH control and ATP-driven metabolism to eradicate rapidly growing glycolytic tumours.

Abstract

Intense interest in the 'Warburg effect' has been revived by the discovery that hypoxia-inducible factor 1 (HIF1) reprogrammes pyruvate oxidation to lactic acid conversion; lactic acid is the end product of fermentative glycolysis. The most aggressive and invasive cancers, which are often hypoxic, rely on exacerbated glycolysis to meet the increased demand for ATP and biosynthetic precursors and also rely on robust pH-regulating systems to combat the excessive generation of lactic and carbonic acids. In this Review, we present the key pH-regulating systems and synthesize recent advances in strategies that combine the disruption of pH control with bioenergetic mechanisms. We discuss the possibility of exploiting, in rapidly growing tumours, acute cell death by 'metabolic catastrophe'.

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Figure 1: The tumour microenvironment presents unique conditions that drive tumour development.
Figure 2
Figure 3: Targeting cellular acidification for tumour cell death: proof of concept.
Figure 4: Membrane transport metabolons: HCO3− and lactate transport.
Figure 5: Physical limitations for the effective reduction of intracellular pH that would be permissive for cell killing.
Figure 6: Potential strategies to target metabolic-pH cellular interactions to induce 'metabolic catastrophe' and achieve tumour cell killing.

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Acknowledgements

Research in the authors' laboratory is financed by European Community (EU7-METOXIA) and French agencies and associations: the Agence Nationale de la Recherche, Ligue Nationale Contre le Cancer (Equipe Labellisée), Institut National du Cancer and grants from the Fondation ARC pour la Recherche sur le Cancer (to S.K.P. and J.C.).

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Authors and Affiliations

  1. Institute for Research on Cancer and Aging of Nice (IRCAN), Equipe Labellisée LNCC, University of Nice-Sophia Antipolis, Centre National de la Recherche Scientifique, INSERM, Centre A. Lacassagne, Nice, 06189, France

    Scott K. Parks & Jacques Pouysségur

  2. Centre Méditerranéen de Médecine Moléculaire (C3M), Équipe Contrôle Métabolique des Morts Cellulaires, INSERM U 1065, Nice, 06204, France

    Johanna Chiche

  3. Centre Scientifique de Monaco, Monaco, MC98000

    Jacques Pouysségur

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Correspondence to Jacques Pouysségur.

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Glossary

Cytostatic

Pertaining to cytostasis, which is basic cellular function without progression through the cell cycle.

H+ dynamics

The interaction between extracellular pH and intracellular pH with respect to acid–base movement between the two compartments and their subsequent cellular effects.

Transport metabolon

A group of enzymatic proteins that interact to achieve a more efficient exchange of metabolites.

Monocarboxylates

Molecules that have one carboxylate group in their structure and require facilitated transport across the plasma membrane; for example, lactate and pyruvate.

Synthetic lethality

The process of targeting multiple proteins and regulatory systems, by which the combined therapy will induce cell death.

Chronic autophagy

Long-term cellular adaptation towards consumption of cellular components.

Ragulator complex

A multiprotein complex that is responsible for the translocation of mTOR complex 1 to the lysosomal surface.

Metabolic dormancy

Suppression of cellular metabolism to provide just the minimal energy required to maintain cytostasis.

Ionophores

Molecules that facilitate the movement of ions across the cell membrane, normally by the formation of pores.

Nernst equilibrium potential

A mathematical formula that describes the equilibrium state of ions between two compartments based on the concentration and electric gradients that exist in the system.

pKa

The acid dissociation constant that indicates the relative strength of a given acid in solution.

Evolutionary game theory

The application of strategic game theory mathematical modelling to the evolutionary progression of a biological system.

Unfolded protein response

A stress response within the cell that responds to misfolded proteins and initiates a cascade that leads to apoptotic cell death.

Metabolic catastrophe

When cellular metabolism is disrupted severely enough to prevent energy (ATP) production and the cell consequently perishes.

ATP crisis

A state in which the cell does not produce enough ATP to meet its energetic demands for survival.

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Parks, S., Chiche, J. & Pouysségur, J. Disrupting proton dynamics and energy metabolism for cancer therapy. Nat Rev Cancer 13, 611–623 (2013). https://doi.org/10.1038/nrc3579

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