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Species-specific mechanisms of tumor suppression are fundamental drivers of vertebrate speciation: critical implications for the ‘war on cancer’

We recently reported our detection of an anthropoid primate-specific, ‘kill switch’ tumor suppression system that reached its greatest expression in humans, but that is fully functional only during the first twenty-five years of life, corresponding to the primitive human lifespan that has characteri...

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Autor principal: Nyce, Jonathan W
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Bioscientifica Ltd 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347260/
https://www.ncbi.nlm.nih.gov/pubmed/30400061
http://dx.doi.org/10.1530/ERC-18-0468
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author Nyce, Jonathan W
author_facet Nyce, Jonathan W
author_sort Nyce, Jonathan W
collection PubMed
description We recently reported our detection of an anthropoid primate-specific, ‘kill switch’ tumor suppression system that reached its greatest expression in humans, but that is fully functional only during the first twenty-five years of life, corresponding to the primitive human lifespan that has characterized the majority of our species' existence. This tumor suppression system is based upon the kill switch being triggered in cells in which p53 has been inactivated; such kill switch consisting of a rapid, catastrophic increase in ROS caused by the induction of irreversible uncompetitive inhibition of glucose-6- phosphate dehydrogenase (G6PD), which requires high concentrations of both inhibitor (DHEA) and G6P substrate. While high concentrations of intracellular DHEA are readily available in primates from the importation and subsequent de-sulfation of circulating DHEAS into p53-affected cells, both an anthropoid primate-specific sequence motif (GAAT) in the glucose-6-phosphatase (G6PC) promoter, and primate-specific inactivation of de novo synthesis of vitamin C by deletion of gulonolactone oxidase (GLO) were required to enable accumulation of G6P to levels sufficient to enable irreversible uncompetitive inhibition of G6PD. Malignant transformation acts as a counterforce opposing vertebrate speciation, particularly increases in body size and lifespan that enable optimized exploitation of particular niches. Unique mechanisms of tumor suppression that evolved to enable niche exploitation distinguish vertebrate species, and prevent one vertebrate species from serving as a valid model system for another. This here-to-fore unrecognized element of speciation undermines decades of cancer research data, using murine species, which presumed universal mechanisms of tumor suppression, independent of species. Despite this setback, the potential for pharmacological reconstitution of the kill switch tumor suppression system that distinguishes our species suggests that ‘normalization’ of human cancer risk, from its current 40% to the 4% of virtually all other large, long-lived species, represents a realistic near-term goal.
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spelling pubmed-63472602019-01-29 Species-specific mechanisms of tumor suppression are fundamental drivers of vertebrate speciation: critical implications for the ‘war on cancer’ Nyce, Jonathan W Endocr Relat Cancer Commentary We recently reported our detection of an anthropoid primate-specific, ‘kill switch’ tumor suppression system that reached its greatest expression in humans, but that is fully functional only during the first twenty-five years of life, corresponding to the primitive human lifespan that has characterized the majority of our species' existence. This tumor suppression system is based upon the kill switch being triggered in cells in which p53 has been inactivated; such kill switch consisting of a rapid, catastrophic increase in ROS caused by the induction of irreversible uncompetitive inhibition of glucose-6- phosphate dehydrogenase (G6PD), which requires high concentrations of both inhibitor (DHEA) and G6P substrate. While high concentrations of intracellular DHEA are readily available in primates from the importation and subsequent de-sulfation of circulating DHEAS into p53-affected cells, both an anthropoid primate-specific sequence motif (GAAT) in the glucose-6-phosphatase (G6PC) promoter, and primate-specific inactivation of de novo synthesis of vitamin C by deletion of gulonolactone oxidase (GLO) were required to enable accumulation of G6P to levels sufficient to enable irreversible uncompetitive inhibition of G6PD. Malignant transformation acts as a counterforce opposing vertebrate speciation, particularly increases in body size and lifespan that enable optimized exploitation of particular niches. Unique mechanisms of tumor suppression that evolved to enable niche exploitation distinguish vertebrate species, and prevent one vertebrate species from serving as a valid model system for another. This here-to-fore unrecognized element of speciation undermines decades of cancer research data, using murine species, which presumed universal mechanisms of tumor suppression, independent of species. Despite this setback, the potential for pharmacological reconstitution of the kill switch tumor suppression system that distinguishes our species suggests that ‘normalization’ of human cancer risk, from its current 40% to the 4% of virtually all other large, long-lived species, represents a realistic near-term goal. Bioscientifica Ltd 2018-10-12 /pmc/articles/PMC6347260/ /pubmed/30400061 http://dx.doi.org/10.1530/ERC-18-0468 Text en © 2019 The authors http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/) .
spellingShingle Commentary
Nyce, Jonathan W
Species-specific mechanisms of tumor suppression are fundamental drivers of vertebrate speciation: critical implications for the ‘war on cancer’
title Species-specific mechanisms of tumor suppression are fundamental drivers of vertebrate speciation: critical implications for the ‘war on cancer’
title_full Species-specific mechanisms of tumor suppression are fundamental drivers of vertebrate speciation: critical implications for the ‘war on cancer’
title_fullStr Species-specific mechanisms of tumor suppression are fundamental drivers of vertebrate speciation: critical implications for the ‘war on cancer’
title_full_unstemmed Species-specific mechanisms of tumor suppression are fundamental drivers of vertebrate speciation: critical implications for the ‘war on cancer’
title_short Species-specific mechanisms of tumor suppression are fundamental drivers of vertebrate speciation: critical implications for the ‘war on cancer’
title_sort species-specific mechanisms of tumor suppression are fundamental drivers of vertebrate speciation: critical implications for the ‘war on cancer’
topic Commentary
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347260/
https://www.ncbi.nlm.nih.gov/pubmed/30400061
http://dx.doi.org/10.1530/ERC-18-0468
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