This note was inspired by a very well-written, easy-to-read, but very long and complicated dissertation on how DHEA prevents cancer, entitled “DETECTION OF A NOVEL, PRIMATE-SPECIFIC ‘KILL SWITCH’ TUMOR SUPPRESSION MECHANISM THAT MAY FUNDAMENTALLY CONTROL CANCER RISK IN HUMANS: AN UNEXPECTED TWIST IN THE BASIC BIOLOGY OF TP53”, by Jonathan W Nyce, In: Endocr Relat Cancer. 2018 Nov; 25(11): R497–R517., Published online 2018 Jun 25. Doi: 10.1530/ERC-18-0241, PMCID: PMC6106910, PMID: 29941676 , at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6106910/
DNA DAMAGE AND MALIGNANT TRANSFORMATION
Our cells are constantly exposed to a variety of cellular stressors and are prone to DNA damage, which can lead to mutation, formation of abnormal genes and eventually, cancer.
Therefore, to protect cells from malignant transformation, the cells’ nuclei carry a special gene called TP53.
TP53 activates other genes, “KILLER GENES”, which can arrest cell metabolism and kill the cell.
This is a natural process called apoptosis, which is good because cells with cancerous potential are destroyed.
However the cells only carry tiny quantities of TP53 and it exists in a dormant, inactive form.
When DNA is damaged, TP53 is induced to accumulate in the cell nucleus and is converted into an active form, which triggers the killer genes to induce cell cycle arrest and/or apoptosis, depending on how much DNA damage has occurred.
If the damage is mild, cell metabolic slowdown permits DNA repair, but if the situation is bad enough, TP53 triggers the killer genes to destroy the cell.
In this way dangerously damaged cells are prevented from cloning themselves and producing daughter cells with damaged DNA and cancer potential.
This idea is supported by the fact that TP53-deficient mice develop spontaneous cancers.
ssociated increase in human cancer risk to that of most other species (dashed red line).
MUTATON OF THE TP53 GENE, ITSELF.
The background point is that TP53 blockade by mutant TP53 depends on an enzyme, glucose-6-phosphate dehydrogenase (G6PD):
G6PD facilitates production of NADP and
NADP inactivates any normal TP53, keeping the abnormal cell alive.
HOW DOES DHEA PREVENT CANCER?
(1) Many years ago (BACK IN THE ’80S), DHEA, the “mother hormone” made by our adrenal glands and our brains, was observed to inhibit spontaneous breast cancer and chemically induced tumors of the lung and colon, in mice.
In mice, it also stopped tumour formation by a carcinogen named DMBA and another called TPA. In fact it was proved to be effective in stopping cancer formation generally, excepting that it promoted liver cancer in rats.
This action of DHEA remained a mystery for decades, but in 2018, Jonathan W Nyce reported a breakthrough: now we know that DHEA potently blocks G6PD, stopping NADP formation. Without NADP, TP53 is activated, and triggers the killer genes.
(2) To put it another way, under normal circumstances G6PD keeps reactive oxygen species low within normal cells. Without G6PD, reactive oxygen species would kill them. So if a mutation produces “wild” cells, the TP53 gene shuts off G6PD and the developing cancer cell is killed by increasing reactive oxygen species.
However some cancer mutations prevent activation of the TP53 gene, so G6PD keeps the oxygen species low in the cancer cell, allowing it to grow and multiply.
DHEA prevents cancer by shutting off G6PD, thus allowing a lethal rise of oxygen species inside the cell which kills the cancer cell.
But our production of DHEA is reduced by 1% every year from the age of 26 and due to this, our protection from cancer-producing mutations gets lower as we get older!
(3) So supplementing DHEA prevents cancer, in most cases.
(4) DHEA may not be effective against all cancers and so what we are talking about here is using it to prevent cancer, not about a guaranteed cure for an existing tumour.
(5) Many of us fail to produce normal amounts of DHEA from the beginning, perhaps because of PTSD in childhood, so when DHEA production starts going down at age 26, high producers start from normal and low producers, from whatever they had in their teens. So by age 80, the highest DHEA producers are down to 10-20% of their original level and poor producers are down to zero.
(6) FAQ:
Do we get cancers because we don’t make enough DHEA?
If I take DHEA as a supplement, will it prevent cancer?
If I have a cancer, will DHEA stop it?
Why don’t all doctors know about this ?
Why is DHEA on the “dangerous drugs list” in Canada?
DHEA: NATURAL production levels in humans, vs. animals.
This graphic representation of DHEA levels in animals and humans was taken from the above referenced paper, by J.W. Nyce, at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6106910/ – see the notes below.
Figure 4, explanation (quotation from text by Dr. J. W. Nyce):
Species-specific kill switch tumor suppression systems targeting G6PD.
In humans, circulating DHEAS (blue and grey lines), and therefore, kill switch function is maintained at optimal levels only up until about age 25 years – the life expectancy for humans for most of our existence as a species. The adrenal androgen-mediated kill switch evolved to provide protection for such short human life spans (blue rectangular prism), and declines sharply thereafter.
Because modern humans live for much longer periods of time, the phenomenon of exponentially increasing cancer risk with increasing age is observed (red line). Species such as the elephant, moose and naked mole rat, which use tumor suppression systems that do not decline with age, experience little or no increased risk of cancer as they age (green line).
(http://www.cancerresearchuk.org/health-professional/cancer-statistics/incidence/age).
Human Lifetime cancer risk of 38.4% (https://www.cancer.gov/about-cancer/understanding/statistics).
Cancer risk of most long-lived mammals = 4%, from Abegglen et al. (2015). Circulating DHEAS levels redrawn after (dePeretti & Forest 1976, Parker & Odell 1980, Vermuelen 1980, Orentreich et al. 1984, Labrie et al. 1997).
Effect of DHEA supplementation, on liability to cancer: taken from Dr. Nyce’s paper, at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6106910/
Figure 5
Potential for pharmacologic extension of adrenal androgen-mediated kill switch. Humans are protected by their natural adrenal androgen-mediated kill switch only until about age 30 (blue rectangular prism). Circulating DHEAS levels decline dramatically thereafter in both men and women (solid blue and grey lines, respectively), resulting in a species-specific exponential increase in cancer risk with increasing age (solid red line).
However, optimum DHEAS levels can be pharmacologically maintained (dashed blue and grey lines) throughout life into old age (green rectangular prism).
If the analogy holds with other long-lived species such as chimpanzees and elephants, in which kill switch mechanisms targeting G6PD are maintained throughout life, pharmacological maintenance of peak DHEAS levels throughout the modern human life span may normalize the age-adjusted cancer risk.
REFERENCES
(1) Role of p53 in Cell Death and Human Cancers: Toshinori Ozaki1 and Akira Nakagawara , Cancers (Basel). 2011 Mar; 3(1): 994–1013.Published online 2011 Mar 3. doi: 10.3390/cancers3010994, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756401/
(2) Detection of a novel, primate-specific ‘kill switch’ tumor suppression mechanism that may fundamentally control cancer risk in humans: an unexpected twist in the basic biology of TP53, Jonathan W Nyce,
2018 Nov;25(11):R497-R517., oi: 10.1530/ERC-18-0241. Epub 2018 Jun 25.
PMID: 29941676, PMCID: PMC6106910, DOI: 10.1530/ERC-18-0241, https://pubmed.ncbi.nlm.nih.gov/29941676/
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