Friday Hope: A Trifecta of p53 Activation: Curcumin, Resveratrol and Berberine

The Spike Protein suppresses p53 tumor suppressor transcription, these natural therapeutics strike back.

The role of curcumin in regulating p53 in BC (Breast Cancer).

One of the reasons for the sudden dramatic increase in worldwide cancers may be due to the Spike Protein of SARS-CoV-2. The Spike Protein interacts with, and suppresses transcription of, tumor suppressor p53. The effect of this suppression results in inhibition of p53-dependent gene activation with potentially deleterious effects, increasing tumorigenesis and tumor progression.

For readers who may not be familiar with p53, here is a brief overview. Indeed, its importance extends far beyond just tumor suppression, and its inhibition may explain far more Spike Protein pathology.

TP53 is a gene that encodes for the p53 tumor suppressor protein, commonly referred to as the “Guardian of the Genome” [1]. Its main biological function appears to involve the protection of the DNA integrity of the cell. TP53 plays additional roles in development, aging and cell differentiation [2]. For example, p53-nullizygous genetic models exhibit phenotypes related to aging, pluripotency and development characterized by early aging onset, induction of cell pluripotency and inability of embryos undergo gastrulation, respectively [[3], [4], [5]]. The p53 protein is a transcription factor that controls the output of many biological processes according to the type of cellular stress signal input. Stress signals known to activate p53 include oncogene activation, DNA damage, and replication stress [6]. In response to these stresses, p53 undergoes post-translational modifications, promotes the transcription of genes involved in specific cell responses according to the stress type thereby controlling the cell's fate [7]. Vastly studied biological processes where p53 has been shown to play a role are cell cycle arrest, senescence, DNA repair, and apoptosis.

Tumor suppressor p53: Biology, signaling pathways, and therapeutic targeting
https://www.sciencedirect.com/science/article/pii/S0304419X21000536

Early in the pandemic, it was noted that the Spike Protein interacted with p53 and other tumor suppressors.

Here we performed bioinformatic analysis to investigate the interaction of S2 subunit protein of SARS-nCoV-2 of novel coronavirus with tumor suppressor proteins p53 and BRCA-1/2. In this short communication we report the interaction between S2 subunit proteins with tumor suppressor proteins for the first time. This preliminary result will open up a new direction to investigate the effect of a novel coronavirus in cancer patients.

S2 subunit of SARS-nCoV-2 interacts with tumor suppressor protein p53 and BRCA: an in silico study
https://www.sciencedirect.com/science/article/pii/S1936523320303065

Ultimately, it was discovered that one of the effects of this interaction was inhibition of its transcription. This, of course, results in inhibiting all genes activated downstream.

We observed that SARS-CoV-2 spike protein interrupts p53-MDM2 protein interaction but did not detect SARS-CoV-2 spike bound with p53 protein in the cancer cells. We further observed that SARS-CoV-2 spike suppresses p53 transcriptional activity in cancer cells including after nutlin exposure of wild-type p53-, spike-expressing tumor cells and inhibits chemotherapy-induced p53 gene activation of p21(WAF1), TRAIL Death Receptor DR5 and MDM2. The suppressive effect of SARS-CoV-2 spike on p53-dependent gene activation provides a potential molecular mechanism by which SARS-CoV-2 infection may impact tumorigenesis, tumor progression and chemotherapy sensitivity.

Transfected SARS-CoV-2 spike DNA for mammalian cell expression inhibits p53 activation of p21(WAF1), TRAIL Death Receptor DR5 and MDM2 proteins in cancer cells and increases cancer cell viability after chemotherapy exposure
https://www.oncotarget.com/article/28582/text/

Given this ability of the Spike Protein to, to put it in chess terms, “remove the defender,” it is important to find ways to counteract this tactic. Fortunately, Nature has provided us with several therapeutics that increase the activation of p53. Let’s talk about three of them. All readily available.

CURCUMIN

Curcumin has the ability to increase p53 to its maximum level.

In healthy human adults, 150 billion (109) cells out of 37.2 trillion (1012) cells will undergo apoptosis on daily basis.81 Curcumin has an anti-proliferative effect and acts as a pro-apoptotic agent in many cancer cell lines.82 It can induce apoptosis by p53 activation and regulation of other apoptotic proteins.83 Specifically, p53 is activated by curcumin after it is translocated into the nucleus of a cancer cell.84 In addition, curcumin upregulates the expression of apoptotic genes such as TRAP3 and MCL-1 and downregulates other genes such as TRAIL and AP13 in BC cells.85

The exposure of human BC cell lines (MCF-7) to cur-cumin induces p53 DNA-binding activity and increases p53 to its maximum level; this is associated with the increased levels of an apoptotic activator known as Bax.86,87 Further studies reported additional upregulated genes by curcumin in this cell line which included many genes induced by the tumor suppressor protein (p53) and which are involved in p53-mediated programmed cell death.88,89

Role of curcumin in regulating p53 in breast cancer: an overview of the mechanism of action
https://pmc.ncbi.nlm.nih.gov/articles/PMC6276637/

RESVERATROL

Resveratrol enhances the expression of p53.

Resveratrol is one of the most promising phytoalexins for use as an anti-cancer agent, which is present in the skin of red grapes and berries. Resveratrol has been demonstrated to modulate a number of signalling pathways that are involved in carcinogenesis. In the present study, the function of resveratrol as a pro-apoptotic agent in colorectal cancer cell lines, including HCT116, CO115 and SW48, was investigated. The results revealed that resveratrol supressed cell viability. Additionally, resveratrol enhanced the expression of tumour protein p53 (p53) and p53 target genes, including Bcl2 associated X, apoptosis regulator and Bcl2 binding component 3 that have a pivotal role in p53-dependent apoptosis. Furthermore, treating cells with resveratrol upregulated SET domain containing lysine methyltransferase 7/9 (SET7/9) expression, which positively regulates p53 through its mono-methylation at lysine 372, compared with untreated cells.

Resveratrol induces p53 in colorectal cancer through SET7/9
https://pmc.ncbi.nlm.nih.gov/articles/PMC6403518/

BERBERINE

Berberine increases the phosphorylation of p53. Phosphorylation of p53 is a critical step in the cellular response to DNA damage and plays a crucial role in tumor suppression.

Berberine (100 μM) inhibited sirtuins significantly (P<0.05) at transcriptional level as well as at translational level. Combination of nicotinamide (sirtuin inhibitor) with berberine potentiated sirtuins inhibition and increased the expression of FoxO1/3a and phosphorylation of p53 tumor suppressor protein. As sirtuins deacetylate non-histone targets including FoxO1/3a and p53, berberine increased the acetylation load of FoxO1/3a and p53 proteins. Acetylated FoxO and p53 proteins transcriptionally activate BH3-only proteins Bim and PUMA (3.89 and 3.87 fold respectively, P<0.001), which are known as direct activator of pro-apoptotic Bcl-2 family protein Bax that culminated into mitochondria mediated activation of apoptotic cascade.

Concurrent acetylation of FoxO1/3a and p53 due to sirtuins inhibition elicit Bim/PUMA mediated mitochondrial dysfunction and apoptosis in berberine-treated HepG2 cells
https://pubmed.ncbi.nlm.nih.gov/26712469/

Given the wide availability of these supplements, they may help protect us when exposed to the Spike Protein of SARS-CoV-2. What I continue to find fascinating and encouraging is that when a natural substance is therapeutic for Spike Protein diseases/injury, it appears to be so for multiple reasons. Of course, this is a work of medical research and not medical advice. Always consult your Primary Care Provider before using any supplement or medicine.

It is a beautiful early Spring Day here in Vermont. After a truly traditional (it was actually COLD and SNOWY) Winter, enjoying a morning pipe to the sounds of the returning birds is uplifting, and fills one with, well, HOPE for the day ahead.

Thank you, as always, for your readership, dialog and support. I truly cannot do this without you. Please have a blessed and hopeful weekend.