Folate & PCa recurrence in the CWR22 model.

[pjoshea13]

New study below [1].

Perhaps of limited interest, but it involves folate - vitamin B9 - which we can theoretically control.

The "CWR22 model" is simply a human PCa xenograft in a mouse. CWR22 "recurs following androgen withdrawal."

"Folate impacts the genome and epigenome by feeding into one-carbon metabolism to produce critical metabolites, deoxythymidine monophosphate and s-adenosylmethionine {SAM, SAMe}."

The area of interest in one-carbon metabolism, IMO, is the SAM (SAMe) cycle:

... methionine --> SAM --> homocysteine --> +folate --> methionine ...

Essentially, methionine provides the methyl for SAM, the universal methyl donor in the body. When SAM drops off its methyl to cells that want it, we are left with homocysteine. The body would like to recycle homocysteine back to methionine. For this it needs a dietary methyl donor. Folate, from greens, is the common source. Folic acid is the synthetic form.

In prostate health, the SAM cycle is a two-edged sword. If the diet does not contain enough methyl, prostate cells will be hypomethylated, & DNA instability can arise - possibly leading to PCa. However, with adequate methyl, PCa cells will suck up an excessive amount of methyl, leading to hypermethylation (& silencing) of the promoter regions of tumor suppressor genes.

Some of us, due to age, cannot absorb sufficient vitamin B12. B12 is an essential cofactor in the SAM cycle. We can eat greens for breakfast, lunch & dinner, but there will not be enough SAM if B12 is insufficient.

{Some years ago, I ran into difficulties when I began injecting B12. I now choose to be borderline deficient.}

"Engrafted mice were fed a folate depleted or supplemented diet beginning at androgen withdrawal, or prior to xenograft implantation. Both folate depletion and supplementation at the time of withdrawal significantly decreased recurrence incidence."

"Folate supplementation prior to xenograft implantation increased time to recurrence, suggesting a protective role."

"By contrast, folate depleted recurrent tumors exhibited transcriptional adaptive responses that maintained high polyamine levels at the expense of increased DNA damage and DNA methylation alterations."

How does folate sufficiency/insufficiency play out in real life?

From 2016 [2]:

"A study was performed with a nested case-control design based on individual participant data from six cohort studies including 6875 cases and 8104 controls; blood collection from 1981 to 2008, and an average follow-up of 8.9 yr"

"... higher folate concentration was associated with an elevated risk of high-grade disease (OR for the top vs bottom fifth: 2.30 ...), with no association for low-grade disease."

"Folate, a vitamin obtained from foods and supplements, is important for maintaining cell health. In this study, however, men with higher blood folate levels were at greater risk of high-grade (more aggressive) prostate cancer compared with men with lower folate levels."

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/292...

Oncotarget. 2017 Oct 20;8(61):103758-103774. doi: 10.18632/oncotarget.21911. eCollection 2017 Nov 28.

Dietary folate levels alter the kinetics and molecular mechanism of prostate cancer recurrence in the CWR22 model.

Affronti HC1, Long MD1, Rosario SR1, Gillard BM2, Karasik E2, Boerlin CS1, Pellerite AJ1, Foster BA2, Attwood K3, Pili R4, Wilton JH2, Campbell MJ5, Smiraglia DJ1.

Author information

1

Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA.

2

Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA.

3

Department of Biostatistics, Roswell Park Cancer Institute, Buffalo, NY, USA.

4

Department of Hematology and Oncology, Indiana University, Indianapolis, IN, USA.

5

College of Pharmacy, Pharmaceutics and Pharmaceutical Chemistry, The Ohio State University, Columbus, OH, USA.

Abstract

Folate impacts the genome and epigenome by feeding into one-carbon metabolism to produce critical metabolites, deoxythymidine monophosphate and s-adenosylmethionine. The impact of folate exposure and intervention timing on cancer progression remains controversial. Due to polyamine metabolism's extraordinary biosynthetic flux in prostate cancer (CaP) we demonstrated androgen stimulated CaP is susceptible to dietary folate deficiency. We hypothesized dietary folate levels may also affect castration recurrent CaP. We used the CWR22 human xenograft model which recurs following androgen withdrawal. Engrafted mice were fed a folate depleted or supplemented diet beginning at androgen withdrawal, or prior to xenograft implantation. Both folate depletion and supplementation at the time of withdrawal significantly decreased recurrence incidence. Folate supplementation prior to xenograft implantation increased time to recurrence, suggesting a protective role. By contrast, folate depleted recurrent tumors exhibited transcriptional adaptive responses that maintained high polyamine levels at the expense of increased DNA damage and DNA methylation alterations. Mining of publically available data demonstrated folate related pathways are exceptionally dysregulated in human CaP, which correlated with decreased time to biochemical recurrence. These findings highlight the potential for novel therapeutic interventions that target these metabolic pathways in CaP and provide a rationale to apply such strategies alongside androgen withdrawal.

KEYWORDS:

androgen withdrawal; castration recurrent prostate cancer; folate; one-carbon metabolism; polyamine metabolism

PMID: 29262598 PMCID: PMC5732764 DOI: 10.18632/oncotarget.21911

[2] ncbi.nlm.nih.gov/pmc/articl...

[BigRich]

I lower my intake of folate rich foods, a couple years ago because of the prevailing research.

Rich

[Kuanyin]

We covered similar ground in your replies to two posts I submitted ("Methylation or Not"; "Homocysteine and Metformin") about a year ago. The difficulty remains how to walk the edge between "hypo-" and "hyper-" methylation. The metformin connection with increased homocysteine exists, as far as my own situation is concerned. I take 7,250 mg of methylcobalamin (split in two doses) and at least 800 mcg of methylfolate (I get additional folate in my multivitamin and from foods). But this has just barely moved me down to the upper range of homocysteine. As I have written twice before, the choice seems to be between cardiovascular disease/Alheimer's vs. possible increase in the aggressiveness of PCa. I eat chicken and fish, but no red meat, so that at my age, I can assume that I am not efficiently absorbing it from the vegetables nor even the supplements (Although my last lab test showed the detectable amount of B-12 in my blood was hundreds, if not thousands, of times the so-called recommended dose.) It appears to be an almost insoluble problem.

[Captain_Dave]

I ran my DNA report and have a SNP rs1801131 which can result in impaired folate metabolism. I guess in this case, it may be a good thing. I do not take B vitamins, but I do eat a large salad every day.

But, if you have the MTHFR, 677CT and 1298AC polymorphisms, you can be more susceptible to prostate cancer.

Article: Association between polymorphisms of folate-metabolizing enzymes and risk of prostate cancer

sciencedirect.com/science/a...

-Dave

[homer13 in reply to Captain_Dave]

I have a double expression of the MTHFR gene, 677CT and 1298AC which means I do not methylate well. My functional physician wants be to take a methyl folate to overcome the deficiency. However, I am on AS and my prostate oncologist has given me specific instructions to avoid all forms of folic acid and folate. I am betwixt and between, but follow my oncologist.

[joeoconnell]

some times i just walk around shakin my head

[j-o-h-n in reply to joeoconnell]

Me Too...

j-o-h-n Sunday 12/24/2017 1:38 PM EST

[cesanon]

Patrick, so does this support vitamin supplementation by vitamin B12? And/or vitamin B9?

[pjoshea13 in reply to cesanon]

I would say that in the U.S. & coutries that followed the FDA mandate of folic acid fortification of grains, it is very difficult to be folate-insufficient. I noticed that following fortification, the standard multivitamin dose was not lowered, so many people are double-dipping. IMO, absolutely not to folic acid supplementation.

For someone who is thinking of B12 supplementation, because of poor uptake (this would have to be sublingual or belly-fat injected) be prepared to see PSA rise. I wouldn't do it unless close to pernicious anemia.

The mouse study seems to support supplementation, but the human study does not.

-Patrick

[cesanon in reply to pjoshea13]

Hmm, Myers put me on B12 (1000 mg 4 x per week, but didn't say why.

[pjoshea13 in reply to cesanon]

If a man is vegan, or nearly so, it's reasonable to prescribe B12, since deficiency is common.

If a man is an omnivore but shows sign of B12 insufficiency, this is likely due to decreased production of intrinsic factor, resulting in poor gut uptake. Oral B12 (not sublingual) would not necessarily be helpful.

-Patrick

[Hidden in reply to pjoshea13]

I take the acid reducer Omeprazole for reflux / hiatal hernia. Dr Oz says that people who take acid reducers, and just older people in general, can run a B12 deficiency. He says that that can lead to issues with brain health that are irreversible. So, I take sublingual B12.

[BigRich in reply to pjoshea13]

Thank you Patrick, for my internist gave me one B-12 injection, for I was in the low range of B-12. I did not know it could raise PSA. How does B-12 injection raise PSA?

Rich

[pjoshea13 in reply to BigRich]

Rich,

B12 is a cofactor in the SAM cycle. As such, it may increase PCa access to methyl & allow the cells to become hypermethylated.

-Patrick

[BigRich in reply to pjoshea13]

Thank you Patrick, I understand the logic after you explained it to me. Since I was only in the low range, I won't need any further B-12 injections.

Rich