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Therapeutic Targeting of Glutamine Metabolism in Colorectal Cancer

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Book cover Colon Cancer Diagnosis and Therapy

Abstract

Colorectal cancer is one of the most commonly diagnosed incurable multifactorial malignancies in the world. To date, there are no promising noninvasive therapeutic tools that have achieved CRC prognosis, survival, and recurrence in clinical settings. We are now very familiar with the most famed term “metabolic reprogramming” that cancer cells preferably employ to meet their rapid bioenergetic and ATP synthesis requirements. Glutamine is the most abundant amino acid in human blood plasma and is known for its significant pleotropic role in the metabolic network.

Here, we exposed the metabolic distortion associated with the metabolism of glutamine in the CRC. Classically, findings have shown that dysregulated glutamine metabolism is significantly associated with CRC growth, survival, metastases, and recurrence. As a result, blocking signaling pathways, enzymes, and transporters associated with glutamine metabolism could be a gold standard strategy to hijack the development of CRC. We hope that this strategy will help to systematically target, manage, and cure CRC.

Yashwant Kumar Ratre and Henu Kumar Verma contributed equally to this work as first authors.

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Abbreviations

968:

5-[3-Bromo-4-(dimethylamino)phenyl]-2,3,5,6-tetrahydro-2,2-dimethyl-benzo[a]phenanthridin-4(1H)-one

ABCA1:

ATP-binding cassette transporter A1

ACSL1:

Adipose acyl-CoA synthetase-1

AGPAT1:

1-Acylglycerol-3-phosphate o-acyltransferase 1

ALL:

Acute lymphoblastic leukemia

ALT:

Alanine aminotransferase

AOA:

Aminooxyacetate

AST:

Aspartate aminotransferase

ATP:

Adenosine triphosphate

BCH:

2-Aminobicyclo-(2,2,1)-heptane-2-carboxylic acid

BPTES:

Bis-2-(5-phenylacetamido-1,3,4-thiadiazol2-yl)ethyl sulfide

CAD:

Carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, dihydroorotase

CB-839:

Telaglenastat

COX2:

Cyclooxygenase-2

CRC:

Colorectal cancer

DNA:

Deoxyribonucleic acid

E2F:

E2 promoter binding factor

EAA:

Essential amino acid

EAAT:

Excitatory amino acid transporter

EGCG:

Epigallocatechin gallate

FADH2:

Flavin adenine dinucleotide

FASN:

Fatty acid synthase

FBP1:

Fructose-1,6-bisphosphatase

FDA:

US Food and Drug Administration

GABA:

Gamma aminobutyric acid

GFAT:

Glutamine fructose-6-phosphate amidotransferase

GLN:

Glutamine

GLS:

Glutaminase

GLU:

Glutamate

GLUD:

Glutamate dehydrogenase

GLUT1:

Glucose transporter 1

GOT2:

Glutamate-oxalate transaminase

GPNA:

L-γ-Glutamyl-p-nitroanilide

GPT2:

Glutamate-pyruvate transaminase

GSH:

Glutathione

HIF-2α:

Hypoxia-inducible factor-2

HK:

Hexokinase

HND:

Hartnup disorder

HSF1:

Heat shock factor 1

JPH203:

(S)-2-amino-3-(4-((5-amino-2-phenylbenzo[d]oxazol-7-yl)methoxy)-3,5-dichlorophenyl

KRAS:

Kirsten rat sarcoma viral oncogene

LDH:

Lactate dehydrogenase

L-DON:

6-Diazo-5-oxo-L-norleucine

MCT4:

Monocarboxylate transporter 4

miRNA:

MicroRNA

MPC1:

Mitochondrial pyruvate carrier 1

mTOR:

Mammalian target of rapamycin

NAD:

Nicotinamide adenine dinucleotide

NADPH:

Nicotinamide adenine dinucleotide phosphate oxidase

NEAA:

Non-essential amino acid

NF-kB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

NH3:

Ammonia

OXPHOS:

Oxidative phosphorylation

p53:

Tumor suppressor 53

PET:

Positron emission tomography

PHGDH:

Phosphoglycerate dehydrogenase

PKCζ:

Protein kinase C zeta

PKM2:

Pyruvate kinase muscle isozyme M2

PPARG:

Peroxisome proliferator-activated receptor gamma

PSAT1:

Phosphoserine aminotransferase 1

R162:

2-Allyl-1-hydroxy-9,10-anthraquinone

Rb:

Retinoblastoma

ROS:

Reactive oxygen species

SAM:

S-Adenosylmethionine

SCD1:

Stearoyl-coenzyme A desaturase 1

SIRT4:

Sirtuin-4

SLC1:

Solute carrier 1

SLC1A5:

Solute carrier family 1 member 5

SLC38:

Solute carrier 38

SLC38A1:

Solute carrier family 38 member 1

SLC38A2:

Solute carrier family 38 member 2

SLC38A3:

Solute carrier family 38 member 3

SLC38A5:

Solute carrier family 38 member 5

SLC38A7:

Solute carrier family 38 member 7

SLC6:

Solute carrier 6

SLC6A14:

Solute carrier family 6 member 14

SLC6A19:

Solute carrier family 6 member 19

SLC7:

Solute carrier 7

SLC7A5:

Solute carrier family 7 member 5

SLC7A6:

Solute carrier family 7 member 6

SLC7A7:

Solute carrier family 7 member 7

SLC7A8:

Solute carrier family 7 member 8

SLC7A9:

Solute carrier family 7 member 9

SSZ:

Sulfasalazine

TCA:

Tricarboxylic acid

TNM:

Tumor node metastasis

V-9302:

2-Amino-4-bis(aryloxybenzyl)aminobutanoic acids

α-KG:

Alpha-ketoglutarate

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    Authors and Affiliations

    1. Department of Biotechnology, Guru Ghasidas Vishwavidyalaya, Bilaspur, Chhattisgarh, India

      Yashwant Kumar Ratre, Arundhati Mehta, Vivek Kumar Soni, Dhananjay Shukla, Alka Ekka & Naveen Kumar Vishvakarma

    2. Institute for Endocrinology and Oncology, “Gaetano Salvatore”, Naples, Italy

      Henu Kumar Verma

    3. Multidisciplinary Research Unit, Maulana Azad Medical College, University of Delhi, New Delhi, India

      Subash Chandra Sonkar

    4. Global Health Equity Scholars Program, University of Arizona, Tucson, AZ, USA

      Shakuntala Mahilkar

    5. Public Health Research Institute of India, Mysore, Karnataka, India

      Shakuntala Mahilkar

    6. Department of Botany, Guru Ghasidas Vishwavidyalaya, Bilaspur, Chhattisgarh, India

      Santosh Kumar Prajapati

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      Naveen Kumar Vishvakarma

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      Dhananjay Shukla

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    Ratre, Y.K. et al. (2021). Therapeutic Targeting of Glutamine Metabolism in Colorectal Cancer. In: Vishvakarma, N.K., Nagaraju, G.P., Shukla, D. (eds) Colon Cancer Diagnosis and Therapy. Springer, Cham. https://doi.org/10.1007/978-3-030-64668-4_15

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