The Folate Receptor [FR].

[pjoshea13]

There has been recent interest in folate/folic acid, the potential effect on PCa proliferation, & the possible benefit of insufficiency. The focus has been on the SAM cycle. Folate/folic acid is a methyl donor in the SAM cycle. SAM delivers methyl to cells that want it. PCa cells are avid methyl users. Hypermethylation in PCa cells silence tumor suppressor genes.

But there is another angle to the folate problem.

Folate is the natural ligand for the folate receptor [FR], but folic acid readily binds to FR too.

When cancer cells rapidy divide they have an increased need for folate. To meet this need, cells will increase the expression of FR on their surface.

In a recent paper that looked at FR expression in circulating PCa cells [1]:

"Folate-receptor positive circulating tumor cells (FR+CTCs) shows an important role in the diagnosis and dynamic monitoring for many solid tumors; however, the application of FR+CTCs in prostate cancer remains unclear." {How come?}

"... FR+CTCs level was consistently high in the prostate cancer patients with different tPSA levels .., and it was significantly higher in the patients with f/tPSA levels <0.16 than in those patients with f/tPSA levels >0.16 ..."

The authors were concerned with FR+CTCs for early diagnosis, but measurement of FR levels in CTCs could identify men who might respond to FR-based therapy.

From an early paper on the subject (Endocyte, US; Israel [2014]) [2]:

"The folate receptor (FR) has been identified as a new molecularly targeted entity, which is highly overexpressed on the surface of a spectrum of solid tumor cells, including ovarian, kidney, lung, brain, endometrial, colorectal, pancreatic, gastric, prostate, testicular, bladder, head and neck, breast, and non-small cell lung cancer. Folic acid conjugation is a novel approach for targeting FR-expressing tissues for personalized treatment."

Endocyte is the developer of Vintafolide {& of "Technetium (99mTc) etarfolatide ... an investigational non-invasive, folate receptor-targeting companion imaging agent" [3]}.

"Vintafolide is designed to deliver the toxic vinblastine drug selectively to cells expressing the folate receptor using folate targeting." [4]

Clearly, for folate plus a lethal conjugate to work, without wiping out normal cells, a minimum number of FRs is required on the target cells. The therapy would thus target only the most aggressive cells. Hopefully with minimal toxicity.

Anyway, the point of this post is that we need to be wary of folic acid in supplements and fortified food. I don't suppose that many of us will overdose on folate from leafy greens, but aggressive PCa needs folate. Flirting with deficiency might slow it down.

This is not medical advice, ot course. For folate deficiency, see: [5].

-Patrick

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

[2] pubmed.ncbi.nlm.nih.gov/254...

[3] en.wikipedia.org/wiki/Techn...

[4] en.wikipedia.org/wiki/Vinta...

[5] en.wikipedia.org/wiki/Folat...

[Hidden]

Would methyl folate be as bad as folic acid?

[pjoshea13 in reply to Hidden]

Methylfolate is immediately bioavailable whereas folic acid must go through a conversion to folate.

Methylfolate is a natural FR ligand so I'd be wary of it.

-Patrick

[Hidden in reply to pjoshea13]

So probably best to be on the low end of normal or maybe even a little below normal? The only vitamins I take are D3 and K2 (my MO agrees that serum D should be 30-50. J-shaped mortality curves so no lower and no higher). I used to take a microdose of a multi but I'm inclined to permanently ditch it.

[PhilipSZacarias]

Another important post. Thank you Patrick. I stopped taking supplements with folate and have found that my semi-Mediterranean diet, which includes good servings of vegetables has been sufficient to maintain circulating B12 levels at lower end of the normal range. Cheers, Phil

[pjoshea13 in reply to PhilipSZacarias]

Thanks Phil!

I hope you are keeping warm up there in the frigid north.

Best, -Patrick

[6357axbz]

Patrick, what is your folate level?

[pjoshea13 in reply to 6357axbz]

On 11/2/21 "Folate (Folic Acid), Serum" was 2.2 ng/mL at LabCorp - ref range >3 ng/mL. (Different range from yours.)

-Patrick

[6357axbz in reply to pjoshea13]

So it’s lower than the recommended range for “normal” people?

[pjoshea13 in reply to 6357axbz]

Yes, it is low for "normal" Americans.

I don't know what is "normal" in countries that do not fortify grains with B9.

In the US:

"The recommended daily amount of folate for adults is 400 micrograms (mcg)."

In Finnish middle-aged men:

"The mean intake of folate in the whole cohort was 256 microg/day"

-Patrick

[cesces]

Very very interesting.

[subliminaldood]

Interesting info... In all the bloodwork that has been done on me I don't remember ever seeing folate serum levels. I did look at my suppliments and turns out I am taking more folate than recommended... My multivitamin contains 167% rda of folate and my MO suggested adding in a B supplement which turns out to also contains 167% of the RDA of folate... I think I'll have them add the Folate Serum test to my blood work next time! I'm very curious if I am taking to much. I certainly have trouble keeping my PSA down.

[maley2711]

evidently among the members of this forum there is a group of biochemists , biologists, and other currently working/retired men with specific scientific backgrounds who are speaking at a level way above the understanding of most men with Pca?

[dhccpa in reply to maley2711]

Yes but many are bilingual and have even translated successfully for me in the past. Plus I'm learning as I go.

[pjoshea13 in reply to maley2711]

None of the above, unfortunately. I have 18 years of PCa, with every day on PubMed. At some point I probably forgot my native language. Will try to do better.

[rscic]

Anyone know of the influence of an abnormality in one of the MTHFR sites (there are 4) in the DNA & the influence on cancer. It is my understanding, Methyl Folate (NOT Folic Acid) is recommended for those who have one or more defects in the 4 MTHFR genes ..... as I recall, at least one defect is fairly common in the general population.

[pjoshea13 in reply to rscic]

See my response to Cigafred.

[cigafred]

As with maley2711 above, much of this is over my head. Please forgive me if I have something out-of-context or just plain stupid.

From this thread I learn that methyl folate is worse than folic acid. Reviewing my notes, I believe Nal wrote some years ago “I use Methyl Folate as it is fully methylated, and can cause no harm.” [Sorry, I do not have the link.] Can anyone sort me out? Thanks.

[pjoshea13 in reply to cigafred]

For those without cancer, and in need of a folate supplement, methylfolate is more natural than folic acid. Folic acid is synthetic. It is generally a good source of folate. Some have questioned the metabolites that are foreign to the body.

"When we take folic acid, we rely on Methylenetetrahydrofolate reductase (MTHFR). This is both a gene and an enzyme that is found throughout our body. It converts folic acid to its active form, L-methylfolate. This process is critical to the body having enough folate." [1]

"Some people have a gene mutation affecting the MTHFR enzyme. For these people, their bodies are unable to convert folic acid to Methylfolate. Therefore, it’s critical that they not take folic acid. They should take Methylfolate instead, to bypass the need to convert the folate." [1]

RSH1 asked:

"Would methyl folate be as bad as folic acid?"

In the context of PCa where we may be trying to reduce folate uptake, methylfolate is worse than folic acid because it is exactly what the cancer wants.

Apologies for introducing a new term: MTHFR. My explanations tend to leave me in a deeper hole.

...

The extracts that follow are from "Folate and Its Impact on Cancer Risk" (US, 2018) [2].

There is mention of MTHFR.

"Folic acid supplementation and higher serum levels are associated with increased risk of prostate cancer."

"There are two well-described MTHFR gene polymorphisms: C677T and A1298C. The C677T variant may occur in close to 20–40% of the population]. Both variants are associated with reduced enzyme activity]. Enzyme efficiency is reduced by up to 45% for the 677CT variant and by up to 70% for 677TT"

"MTHFR 677TT may have a protective effect against ... aggressive forms of prostate cancer ... among Asians"

From an earlier study "Relationship between methylenetetrahydrofolate reductase C677T and A1298C genotypes and haplotypes and prostate cancer risk and aggressiveness" (US, 2004) [3]

"When stratifying the study population by disease aggressiveness at diagnosis, the C677T variant was positively associated with risk among men with less advanced disease ... In contrast, when looking at men with more advanced disease, the C677T variant was inversely associated with risk.., whereas the A1298C variant was positively associated with risk ...

"Furthermore, the 677T-1298A haplotype was positively associated with prostate cancer among men with less advanced disease ... and inversely associated with risk of more advanced disease ...

"Our findings suggest that 677T and 1298A, or another variant on their haplotype, may be associated with a reduced risk of progression to more advanced prostate cancer."

Presumably, methylfolate would negate such protection.

-Patrick

[1] tespovitamins.com/the-benef...

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

[3] pubmed.ncbi.nlm.nih.gov/152...

[cigafred in reply to pjoshea13]

Having you and a couple of the others here is like having my own personal cancer concierge. Many thanks.

[j-o-h-n]

Am I intime for folate?.........

Good Luck, Good Health and Good Humor.

j-o-h-n Friday 01/21/2022 3:19 PM EST

[CurrentSEO]

Hi Patrick, I pay attention to my level of B-12 from the diagnosis and manage to have it in a low acceptable range. I do not supplement with vitamins B at all (except a short period with b-12) and since I stopped being vegan and added fish and seafood to my diet ... it is not necessary to supplement with B-12. I do not eat bread and any fortified products and I eat a lot of fiber and especially fruits.

B-12 being controlled, however my folic acid tests are fluctuating in a range between 13 ng/mL and 18 ng/mL - that is obviously high.

Is there any way I can reduce folate level by supplements or food besides drinking alcohol (I'm planning to start on a daily red wine only in October)?

Thank you!

[pjoshea13 in reply to CurrentSEO]

Since folate is a vitamin, it can only come from food & supplements, so it should be easy to control, in that respect.

In the US & in countries that followed the FDA mandate, it can be difficult to avoid folic acid. You eat no bread or fortified products (note that rice is fortified), so why would your folate level ever be elevated?

Check out the "Sources" section in:

en.wikipedia.org/wiki/Folat...

There were a few surprises I had forgotten about.

Otherwise, maybe you are not using it up at the normal rate?

The SAM cycle is somewhat complex, in that it depends not just on a methyl donor, but also on cofactors. However, elevated homocysteine would be indicatative of a dysfunctional SAM cycle.

You say that B12 is under control because you now get enough from marine sources. But do you know that it is being absorbed? (If homocysteine is low, B12 uptake is probably fine.)

You are planning on starting daily red wine in 9 months? Do I really need to say this to a fellow PCa sufferer? Carpe Diem!!! LOL.

-Patrick

[CurrentSEO]

Thank you Patrick!

I test regularly for b-12 and folate, B-12 since I added fish and seafood fluctuate between 170-240 pg/mL. However I haven’t tested for …. homocysteine. Will do that in a week.

I’m eating not processed organic food only (except when in a restaurant) including rice, cereals Ezekiel brand and always check the labels so there are no added “benefits” of added folate, B-12, Iron or other minerals.

I do consume a lot of seeds a variety of nuts. Looks like I will stop sunflower seeds and walnuts and limit nuts and seeds intake to 3-4 times a week instead of daily.

I knew long ago not to supplement with Bs, but haven’t really pay attention fir the high level of folate.

P.S. Red wine resumption😅. I do mostly live in the Now. I’m abstaining from sex and alcohol till October for a lack of better explanation/word “religious” reasons.

Funny that when I was drinking almost daily 2-3 servings of whiskey or tequila plus often extra wine and champagne - cancer was under control without any treatments or meds for more than a decade. I guess alcohol was keeping folate in check 😂. Then I stoped drinking for 5 months as I was battling GERD and helicobacter pylori (which often cause of a GERD) … and bum PSA 1,600+ and doubling time 23-25 days. Correlation is not causation… but makes you wonder😉