Species specificity of an adrenal androgen-mediated kill-switch triggered by p53 inactivation

Submitted: 1 May 2017
Accepted: 18 July 2017
Published: 30 October 2017
Abstract Views: 1335
PDF: 540
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Authors

Glucose-6-phosphate dehydrogenase (G6PD) is an oncoprotein that is regulated by the p53 tumor suppressor. Mutant p53 loses the ability to inhibit G6PD, and loss of G6PD control clearly plays a role in oncogenesis. The steroid hormone precursor dehydroepiandrosterone (DHEA) is an endogenous uncompetitive inhibitor of G6PD. In humans, and a few other species, the sulfated circulatory form of DHEA (DHEAS) is present at extremely high concentrations – much higher than can be accounted for by DHEA’s function as a precursor to steroid hormones. Uncompetitive inhibition is extremely rare in natural systems because it is irreversible in the presence of high concentrations of substrate and inhibitor. What has gone unappreciated is that such uncompetitive inhibition can quickly lead to cell death when the target is an obligatory housekeeping gene such as G6PD. Cells with inactivated p53 not only lose control over G6PD, but also over hexokinase (HK), the enzyme that converts glucose into glucose-6-phosphate (G6P), the substrate of G6PD. Furthermore, loss of p53 function de-represses NFκB activity, resulting in the upregulation of steroid sulfatase (SS) which converts circulating DHEAS into active DHEA. We propose that inactivation of p53 rapidly elevates G6P and DHEA concentrations in affected cells, driving uncompetitive inhibition of G6PD to lethal irreversibility. In animals with circulating DHEAS, this kill-switch mechanism may prevent most cases of p53 inactivation from becoming tumorigenic. Tumors would thus represent instances in which this mechanism had not been triggered, but which might still be triggered by application of DHEA sufficient to uncompetitively inhibit tumor G6PD. To test this hypothesis, we performed a pilot study in which dogs with cardiac hemangiosarcoma were treated with high dose (HD) DHEA supplemented with isoprene precursors to maintain geranylation of Rac GTPase. Tumor regression and longevity observed in these dogs supported the concept that some tumors retain extraordinary sensitivity to uncompetitive inhibition by DHEA.

Dimensions

Altmetric

PlumX Metrics

Downloads

Download data is not yet available.

Citations

Supporting Agencies

National Cancer Institute (CA47217-01), and the DeCecco Family Foundation. The diagnostic skills of Dr. Steven Liebl, DVM, and Dr. Nicolas Russell, ACVIM (Board certified cardiologist) are gratefully acknowledged.
Jonathan W. Nyce, Advanced Canine Genetic Testing, Collegeville, PA
Director of clinical research

How to Cite

Nyce, J. W. (2017). Species specificity of an adrenal androgen-mediated kill-switch triggered by p53 inactivation. Translational Medicine Reports, 2(1). https://doi.org/10.4081/tmr.6773