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

Abstract

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.

Components of the human-specific, p53-mediated “kill switch” tumor suppression mechanism are usurped by human tumors, creating the possibility of therapeutic exploitation

“…The existence of species-specific mechanisms of tumor suppression requires reappraisal of common laboratory animals in the construction of model systems with which to study human cancer. We argue that, because of the existence of such species-specific mechanisms of tumor suppression, one vertebrate species cannot be used to construct a valid model system of cancer in another vertebrate species [ 1 , 3 ] . However, although imperfect, dogs with spontaneous cancer offer perhaps the best non-human animal model available, because they possess a rudimentary form of an otherwise anthropoid primate-specific “kill switch” tumor suppression system based upon circulating DHEAS (which may have enabled their co-habitation with humans, and resistance to co-exposure to polycyclic aromatic hydrocarbons resulting from human harnessing of fire) [ 1 , 3 ] .…”

“…We argue that, because of the existence of such species-specific mechanisms of tumor suppression, one vertebrate species cannot be used to construct a valid model system of cancer in another vertebrate species [ 1 , 3 ] . However, although imperfect, dogs with spontaneous cancer offer perhaps the best non-human animal model available, because they possess a rudimentary form of an otherwise anthropoid primate-specific “kill switch” tumor suppression system based upon circulating DHEAS (which may have enabled their co-habitation with humans, and resistance to co-exposure to polycyclic aromatic hydrocarbons resulting from human harnessing of fire) [ 1 , 3 ] . We have demonstrated that failed “kill switches” can still be triggered to fire in some canine tumors, and have proposed a collaboration with NCI to expand those studies in canine cancer to include the strategies discussed above, employing fluasterone sulfate for STS-expressing canine tumors, and with FDG to exploit the “kill switch” kinetics of irreversible uncompetitive inhibition of G6PD in canine tumors that avidly take up FDG.…”

“…While high intracellular levels of DHEA can be generated by the import of DHEAS from the circulation, the accumulation of high intracellular levels of glucose-6-phosphate (G6P) substrate are impossible in non-anthropoid species because the synthesis of vitamin C via gulonolactone oxidase (GLO), and the activity of glucose-6-phosphatase (G6PC), both act as “sinks” for G6P, preventing such accumulation. Anthropoid primates, including humans, show an Alu transposon-mediated inactivation of GLO and a specific promoter modification in the G6PC promoter that together enable G6P to accumulate in p53-affected cells, sufficient to drive the uncompetitive inhibition of G6PD by DHEA to irreversibility [ 3 ] . Irreversible uncompetitive inhibition of G6PD by DHEA in cells with inactivated p53 thus leads to a catastrophic increase in ROS, extinguishing such cells at the single cell stage before they have the opportunity to grow into the heterogeneous tumor cell populations that have made cancer incurable up to now.…”

Alert to US physicians: DHEA, widely used as an OTC androgen supplement, may exacerbate COVID-19

“…G6PD is the main source for the synthesis of NADPH required for selenoprotein synthesis, a group of proteins most of which act as oxidoreductases to detoxify reactive oxygen species (ROS) (Zhang et al 2020); and for FSP1-mediated reduction of ubiquinone to ubiquinol, required for the prevention of ironmediated ferroptosis (Dixon et al 2012). Uncompetitive inhibition of G6PD by DHEA thus has the potential to induce ROS/ferroptosis-mediated cell death, and this has been proposed as the basic element of a primate-specific, 'kill switch' tumor suppression mechanism (Nyce 2018(Nyce , 2019(Nyce , 2020. DHEA'a ability to powerfully inhibit G6PD has special relevance to the COVID-19 pandemic because reduction in normal G6PD activity has been shown to sensitize human cells to coronavirus infection (Wu et al 2008).…”

The Purpose of Adrenarche Is Tumor Suppression: Identification of a Novel, Human-Specific, Kill-Switch Tumor Suppression Mechanism Dependent upon the Dramatic Adrenarchal Rise of Adrenal Androgens

“…This laboratory has recently identified a human-specific, "kill switch" tumor suppression mechanism that is dependent upon the DHEAS that is synthesized and secreted into the circulation at adrenarche [11][12][13]. In brief, circulating DHEAS is specifically imported into cells that have suffered a tumorigenic lesion-typically in the p53 tumor suppressor gene.…”