Species-specific mechanisms of tumor suppression: trouble in paradigm.

A here-to-fore unknown tumor suppression mechanism reached its greatest expression in humans, having evolved to protect during the twenty-five-year lifespan of primitive humans. It depends upon high levels of circulating DHEAS and its importation into cells that have experienced inactivation of TP53, whereupon DHEAS is desulfated to DHEA, an uncompetitive inhibitor of Glucose-6-phosphate Dehydrogenase (G6PD). Uncompetitive inhibition of G6PD becomes irreversible in the presence of high levels of inhibitor and substrate (G6P). We reported an anthropoid primate-specific sequence motif in the Glucose-6-phosphatase (G6PC) promoter that enables intercellular G6P to accumulate to concentrations sufficient to induce irreversible uncompetitive inhibition of G6PD. We now conclude that inactivation of Gulonolactone Oxidase (GLO), a primate-specific event resulting in vitamin C auxotrophy, also contributed to kill switch evolution by enabling G6P accumulation. Unique mechanisms of tumor suppression appear to distinguish all vertebrate species, preventing 'one vertebrate species from serving as a valid model system for another'. This unrecognized element of speciation undermines decades of cancer research data, using murine species, that 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.