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Metabolic changes associated with tumor metastasis, part 2: Mitochondria, lipid and amino acid metabolism

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Abstract

Metabolic alterations are a hallmark of cancer controlling tumor progression and metastasis. Among the various metabolic phenotypes encountered in tumors, this review focuses on the contributions of mitochondria, lipid and amino acid metabolism to the metastatic process. Tumor cells require functional mitochondria to grow, proliferate and metastasize, but shifts in mitochondrial activities confer pro-metastatic traits encompassing increased production of mitochondrial reactive oxygen species (mtROS), enhanced resistance to apoptosis and the increased or de novo production of metabolic intermediates of the TCA cycle behaving as oncometabolites, including succinate, fumarate, and d-2-hydroxyglutarate that control energy production, biosynthesis and the redox state. Lipid metabolism and the metabolism of amino acids, such as glutamine, glutamate and proline are also currently emerging as focal control points of cancer metastasis.

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Notes

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Abbreviations

αKG:

α-Ketoglutarate

Aco:

Aconitase

ACLY:

ATP-citrate lyase

CoA:

Coenzyme A

CS:

Citrate synthase

d-2HG:

d-2-Hydroxyglutarate

EMT:

Epithelial-to-mesenchymal transition

ETC:

Electron transport chain

eSC:

Embryonic stem cell

FASN:

Fatty acid synthase

FH:

Fumarate hydratase

GDH:

Glutamate dehydrogenase

GLS:

Glutaminase

HGFR:

Hepatocyte growth factor receptor

HIF-1:

Hypoxia-inducible factor-1

IDH:

Isocitrate dehydrogenase

KEAP1:

Kelch-like ECH-associated protein 1

KRAS:

Kirsten Rat Sarcoma

MCL-1:

Myeloid cell leukemia-1

mtROS:

Mitochondrial reactive oxygen species

mTORC1:

Mammalian target of rapamycin complex 1

NF-κB:

Nuclear factor-κB

NRF2:

Nuclear factor-like 2

OXPHOS:

Oxidative phosphorylation

PGC-1:

Peroxisome proliferator-activated receptor γ coactivator-1

PHD:

Prolylhydroxylase

PI3K:

Phosphoinositide 3-kinase

PKB/Akt:

Protein kinase B

ROS:

Reactive oxygen species

SDH:

Succinate dehydrogenase

SOD:

Superoxide dismutase

SRC2:

Steroid receptor coactivator 2

SREBP:

Sterol regulatory element-binding protein

STAT3:

Signal transducer and activator of transcription 3

TCA (cycle):

Tricarboxylic acid (cycle)

TET (enzyme):

Ten-eleven translocation (enzyme)

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Acknowledgments

Work at the authors’ lab is supported by a Starting Grant from the European Research Council (ERC No. 243188 TUMETABO), Interuniversity Attraction Pole (IAP) grant #UP7-03 from the Belgian Science Policy Office (Belspo), an Action de Recherche Concertée from the Communauté Française de Belgique (ARC 14/19-058), the Belgian Fonds National de la Recherche Scientifique (F.R.S.-FNRS), the Télévie, the Belgian Fondation contre le Cancer (2012-186), the Belgian Federal Agency for Nuclear Control (FANC-AFCN), the Louvain Foundation and the UCL Fonds Spéciaux de la Recherche (FSR). Pierre Sonveaux is a F.R.S.-FNRS Research Associate, Paolo E. Porporato a F.R.S.-FNRS Postdoctoral Fellow and Valéry L. Payen a F.R.S.-FNRS PhD Fellow. Bjorn Baselet is a grantee of the Belgian Nuclear Research Center (SCK·CEN).

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    Authors and Affiliations

    1. Pole of Pharmacology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCL), Avenue Emmanuel Mounier 52, box B1.53.09, 1200, Brussels, Belgium

      Paolo E. Porporato, Valéry L. Payen, Bjorn Baselet & Pierre Sonveaux

    2. Radiobiology Unit, Belgian Nuclear Research Centre, SCK·CEN, 2400 Mol, Belgium

      Bjorn Baselet

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    1. Paolo E. Porporato
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    2. Valéry L. Payen
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    3. Bjorn Baselet
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    4. Pierre Sonveaux
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    Correspondence to Pierre Sonveaux.

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    P. E. Porporato and V. L. Payen equally contributed to this manuscript.

    Submitted as a companion paper to “Payen VL, Porporato PE, Baselet B, Sonveaux P. Metabolic changes associated with tumor metastasis, part 1: Tumor pH, glycolysis and the pentose phosphate pathway.”

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    Porporato, P.E., Payen, V.L., Baselet, B. et al. Metabolic changes associated with tumor metastasis, part 2: Mitochondria, lipid and amino acid metabolism. Cell. Mol. Life Sci. 73, 1349–1363 (2016). https://doi.org/10.1007/s00018-015-2100-2

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    • DOI: https://doi.org/10.1007/s00018-015-2100-2

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