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Dual contribution of the mTOR pathway and of the metabolism of amino acids in prostate cancer

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Abstract

Background

Prostate cancer is the leading cause of cancer in men, and its incidence increases with age. Among other risk factors, pre-existing metabolic diseases have been recently linked with prostate cancer, and our current knowledge recognizes prostate cancer as a condition with important metabolic anomalies as well. In malignancies, metabolic disorders are commonly associated with aberrations in mTOR, which is the master regulator of protein synthesis and energetic homeostasis. Although there are reports demonstrating the high dependency of prostate cancer cells for lipid derivatives and even for carbohydrates, the understanding regarding amino acids, and the relationship with the mTOR pathway ultimately resulting in metabolic aberrations, is still scarce.

Conclusions and perspectives

In this review, we briefly provide evidence supporting prostate cancer as a metabolic disease, and discuss what is known about mTOR signaling and prostate cancer. Next, we emphasized on the amino acids glutamine, leucine, serine, glycine, sarcosine, proline and arginine, commonly related to prostate cancer, to explore the alterations in their regulatory pathways and to link them with the associated metabolic reprogramming events seen in prostate cancer. Finally, we display potential therapeutic strategies for targeting mTOR and the referred amino acids, as experimental approaches to selectively attack prostate cancer cells.

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Abbreviations

PCa:

Prostate cancer

PSA:

Prostate serum antigen

ADT:

Androgen deprivation therapy

AR:

Androgenic receptor

CRPC:

Castration-resistant prostate cancer

BMI:

Body mass index

TCA:

Tricarboxylic acid

OXPHOS:

Oxidative phosphorylation

MR:

Magnetic resonance

HFD:

High fat diet

α-KG:

α-Ketoglutarate

PIN:

Prostatic intraepithelial neoplasia

GLUT:

Glucose transporter

HK:

Hexokinase

OCR:

Oxygen consumption rate

ATP:

Adenosine triphosphate

SREBP:

Sterol regulatory element binding protein

ROS:

Reactive oxygen species

mTOR:

Mammalian target of rapamycin

AMPK:

AMP-activated protein kinase

mTORC1:

mTOR complex 1

mTORC2:

mTOR complex 2

RAPTOR:

Rapamycin-sensitive adaptor protein of mTOR

RICTOR:

Rapamycin-insensitive companion of mTOR

4E-BP1:

Eukaryotic initiation factor 4E binding protein 1

p70-S6K:

P70 S6 kinase

PDCD4:

Programmed cell death 4

PKM2:

Pyruvate kinase M2

SGK:

Serum glucose kinase

PKC:

Protein kinase C

PKB:

Protein kinase B

TSC:

Tuberous sclerosis complex

PDPK1:

Phosphoinositide-dependent protein kinase 1

PPP:

Pentose phosphate pathway

TCGA:

The Cancer Genome Atlas

FASN:

Fatty acid synthase

GDPH:

Glycerophosphate dehydrogenase

GS:

Glutamine synthetase

GLS:

Glutaminase

GAC:

Glutaminase C

GAB:

Glutaminase B

GLUD1:

Glutamate dehydrogenase 1

BPH:

Benign prostatic hyperplasia

NAA:

N-acetyl aspartate

NAAG:

N-acetyl aspartyl glutamate

GOT1:

Aspartate aminotransferase/glutamic-oxaloacetic transaminase 1

IDH:

Isocitrate dehydrogenase

EVs:

Extracellular vesicles

BCAA:

Branched-chain amino acid

LRR:

Leucine-rich repeat

LAT:

L-type amino acid transporter

POV1:

Prostate cancer overexpressed gene 1

p-AKT:

Phosphorylated AKT

IFN:

Interferon

SLFN5:

Schlafen family member 5

ATF4:

Activating transcription factor 4

SILAC:

Stable isotope labeling by amino acids in cell culture

FDA:

Food and Drug Administration

BCATS:

Branched-chain aminotransferases

SGCOP:

Serine, glycine, one carbon pathway

SAM:

S-adenosylmethionine

PSAT1:

Phosphoserine aminotransferase 1

PHGDH:

Phosphoglycerate dehydrogenase

LC-MS:

Liquid chromatography-mass spectrometry

GC-MS:

Gas chromatography-mass spectrometry

GNMT:

Glycine N-methyltransferase

P5C:

Δ1-Pyrroline-5-carboxylate

POX:

Proline oxidase

PRODH:

Proline dehydrogenase

LC:

Liquid chromatography

OCT:

Ornithine carbamoyl transferase

ASS1:

Argininosuccinate synthetase

TEAD:

Transcriptional enhanced associate domain

EMT:

Epithelial-to-mesenchymal transition

PRMT5:

Protein arginine methyltransferase 5

CARM1:

Coactivator-associated arginine methyltransferase

PKCλ/ι:

PKC lambda/iota

NEPC:

Neuroendocrine prostate cancer

MAPK:

MAP kinase

ERK:

Extracellular signal-regulated protein kinase

PLCε:

Phospholipase epsilon

PSHP:

Phosphoserine phosphatase

CDK:

Cyclin-dependent kinase

PDX:

Patient-derived xenograft

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Acknowledgements

Alejandro Schcolnik-Cabrera would like to thank the Fonds de Recherche Santé du Québec (FRQS) for the postdoctoral fellowship provided (307595). Daniel Juárez-López would like to thank CONACyT-México for the scholarship provided (388590/288329), and to the Programa de Posgrado en Ciencias Biológicas, Plan de Doctorado en Ciencias Biológicas, UNAM.

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Authors and Affiliations

  1. Département de Biochimie et Médicine Moléculaire, Université de Montréal, Succursale Centre-Ville, Montréal, QC, C.P. 6128, Canada

    Alejandro Schcolnik-Cabrera

  2. Hôpital Maisonneuve-Rosemont Research Centre, 5415 Assumption Blvd, Montréal, QC, H1T 2M4, Canada

    Alejandro Schcolnik-Cabrera

  3. Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México, Av. Ciudad Universitaria 3000, C.P. 04510, Coyoacán, Ciudad de Mexico, Mexico

    Daniel Juárez-López

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  1. Alejandro Schcolnik-Cabrera
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Conceptualization: Alejandro Schcolnik-Cabrera; literature search: Alejandro Schcolnik-Cabrera; writing: Alejandro Schcolnik-Cabrera and Daniel Juárez-López; image preparation: Daniel Juárez-López. Both authors read and approved the final manuscript.

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Correspondence to Alejandro Schcolnik-Cabrera.

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Schcolnik-Cabrera, A., Juárez-López, D. Dual contribution of the mTOR pathway and of the metabolism of amino acids in prostate cancer. Cell Oncol. 45, 831–859 (2022). https://doi.org/10.1007/s13402-022-00706-4

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