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

Abstract

We recently reported our detection of an anthropoid primate-specific, adrenal androgen-dependent, “kill switch” tumor suppression mechanism that is triggered by the inactivation of the p53 tumor suppressor. This mechanism reached its highest expression only in humans as a result of the human-specific harnessing of fire, which resulted in an extraordinary increase in exposure to polycyclic aromatic hydrocarbons. This “kill switch” becomes inoperative in modern humans once they exceed the primitive human lifespan of 25-30 years, because lifespan has more than tripled in modern times, but the secretion curve for dehydroepiandrosterone sulfate remains fixed at the level required for the primitive human lifespan. Components of this “kill switch” are consequently usurped by human tumors, and these are already targets for inhibition in cancer chemotherapy. Here, we suggest a different strategy: using the usurped components of the kill switch to activate prodrugs, rather than as targets for inhibition. This strategy is in its infancy, but has the potential to enable more tumor-specific cytotoxicity, which the inhibition strategy generally cannot achieve. Detection of the usurpation of kill switch elements in liquid biopsy analyses enables the collection of information relevant to this new class of tumor biomarkers without the necessity of invasive tissue biopsy.

Keywords

p53 / TP53 / dehydroepiandrosterone / dehydroepiandrosterone sulfate

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