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Canceromics Studies Unravel Tumor’s Glutamine Addiction After Metabolic Reprogramming

  • Chapter
Tumor Cell Metabolism

Abstract

Metabolism is fundamental to cell survival, growth, and behavior. Tumor cells have an enhanced demand for nutrients which provide biosynthetic building blocks and cellular energy to sustain their proliferative status. Altered metabolism is a hallmark of cancer. The term metabolic reprogramming has been coined to describe the whole range of metabolic abnormalities accompanying tumorigenesis and metastasis. Increased glutamine uptake and glutaminolysis are key metabolic traits that have been consistently found on a wide range of human and experimental cancers. Glutaminase proteins control the first step in the glutaminolytic process: the conversion of glutamine to glutamate and ammonium ions. Glutaminase expression has been correlated with malignancy and growth rate on a great variety of tumors. Recent works are now starting to uncover the differential expression of glutaminase isoenzymes and their regulation by oncogenes and tumor suppressor genes. In parallel, glutaminase isoforms are attracting great interest as novel cancer chemotherapeutic targets. The focus of this chapter will highlight the role of glutamine addiction in tumor biology with particular emphasis on the interaction between the host and the tumor.

Dedicatory: This work is dedicated to Professor Dr. Ignacio Núñez de Castro on occasion of his 77th birthday. His early vision on the relevance of glutamine and glutaminases in cancer growth and proliferation, along with his seminal metabolic works in experimental tumors, paved the way for fertile research lines now being developed for many of us who had the privilege of being inspired by his example and master guidance.

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Abbreviations

α-KG:

2-Oxoglutarate

APC/C:

Anaphase-promoting complex/cyclosome

CE-MS:

Capillary electrophoresis coupled to mass spectrometry

EAA:

Essential amino acids

EATC:

Ehrlich ascites tumor cells

EGF:

Epidermal growth factor

FMNL3:

Formin-like protein 3

GA:

Glutaminase

GDH:

Glutamate dehydrogenase

GFAT:

Glutamine:fructose-6-P amidotransferase

GIP:

Glutaminase-interacting protein

GlcN-6-P:

Glucosamine-6-phosphate

GS:

Glutamine synthetase

GSH:

Reduced glutathione

GSSG:

Oxidized glutathione

HBP/HEX:

Hexosamine biosynthetic pathway

HDAC:

Histone deacetylase

H3K4me3:

Histone H3 trimethyl Lys4

HMGA2:

High-mobility-group AT-hook protein 2

IDH1:

Isocitrate dehydrogenase 1

IMM:

Inner mitochondrial membrane

LDH:

Lactate dehydrogenase

MCA:

Methylcholanthrene induced

mTORC1:

Mammalian target of rapamycin complex 1

MUC-1:

Mucin 1

NEDD-4:

Neural precursor cell-expressed developmentally downregulated gene 4

NF-κB:

Nuclear factor-kappa B

NMR:

Nuclear magnetic resonance

O-GlcNAc:

O-Linked N-acetyl-glucosamine

OXPHOS:

Oxidative phosphorylation

PFKFB3:

6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase, isoform 3

PK:

Pyruvate kinase

PPP:

Pentose phosphate pathway

ROS:

Reactive oxygen species

SCF:

Skp1/cullin/F-box

SMP:

Submitochondrial particles

TCA:

Tricarboxylic acid cycle

TGF-β:

Transforming growth factor beta

UDP-GlcNAc:

UDP-N-acetylglucosamine

USP-15:

Ubiquitin carboxyl-terminal hydrolase 15

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Acknowledgements

We are grateful to everybody in the Canceromics group at University of Málaga for creating most of the own work described in this chapter. This work was supported by grants SAF2010-17573 from the Ministry of Science and Innovation of Spain, Excellence Grant CVI-6656 from the regional Andalusian government (Junta de Andalusia), and Grant RD06/1012 of the RTA RETICS (Red Temática de Investigación Cooperativa en Salud) network from the Spanish Health Institute Carlos III. We also wish to thank Prof. G. Lubec for the important support obtained from his Neuroproteomics lab (Vienna) and to Dr. H. Leban for thoughtful discussions.

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Authors and Affiliations

  1. Facultad de Ciencias, Canceromics Lab, Departamento de Biología Molecular y Bioquímica, Universidad de Málaga, Málaga, 29071, Spain

    Javier Márquez, José M. Matés, Francisco J. Alonso, Mercedes Martín-Rufián, Carolina Lobo & José A. Campos-Sandoval

  2. Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain

    Javier Márquez, José M. Matés, Francisco J. Alonso, Mercedes Martín-Rufián, Carolina Lobo & José A. Campos-Sandoval

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  1. Javier Márquez
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  2. José M. Matés
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  5. Carolina Lobo
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Correspondence to Javier Márquez .

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  1. Inst. of Veterinary Physiology and Bioch, Justus-Liebig-University of Giessen, Gießen, Hessen, Germany

    Sybille Mazurek

  2. Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

    Maria Shoshan

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Márquez, J., Matés, J.M., Alonso, F.J., Martín-Rufián, M., Lobo, C., Campos-Sandoval, J.A. (2015). Canceromics Studies Unravel Tumor’s Glutamine Addiction After Metabolic Reprogramming. In: Mazurek, S., Shoshan, M. (eds) Tumor Cell Metabolism. Springer, Vienna. https://doi.org/10.1007/978-3-7091-1824-5_12

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