Subversion

[Guest guest]

PDT & et.,

The first paper by King, Beer et al(1), describes the effect of 24

hydroxylase on the role of vitamin D in maintaining a host of normal

functions. In a nutshell: remove protective vitamin D and increase the

risk (amongst other things) of prostate cancer. Subversion.

The second paper is an old favourite of mine co-authored by

Gustafsson(2) at Karolinska in 2002, showing that the pure DHT

derivative 5alpha-androstane-3beta,17beta-diol (3betaAdiol) has a

protective function on prostatic growth and development in the rat.

Another Gustafsson from the same Karolinska Institute in 2007

underlines the importance of the earlier animal study, identifying

methylation of the CYP7B1 promoter region as the cause of CYP7B1

overexpression. [ After you have read #1 & #2, can you see where I am

going with this one yet ? ] Finally, some real-world corroborative

ecological data (4) showing genetic differences in CYP7B1

polymorphisms between Swedes and Koreans. Different allele frequencies

in the populations correspond with different rates of PC in the two

ethnic groups.

My view is that just as 24 hydroxylase subverts vitamin D from its

protective function, so CYP7B1 subverts the androgen derivative of

DHT, 3betaAdiol from its protective function. Subversion.

So now along with looking at ways to prevent 24 hydroxylase from

subverting vitamin D in my system, I am looking at ways to prevent

CYP7B1 from subverting 3betaAdiol in my system. I am not on any kind

of hormone block, so the task should be relatively easy. I should add

that even for someone on 'castration-lite' (finasteride, dutasteride)

or full CHB3, the role of 3betaAdiol is vital in maintaining ERbeta

functionality. Without ERbeta as a moderating influence on prostate

cancer cells, the disease eventually recurs with a non-functional

ERbeta and an active ERalpha. Read Gustafsson senior's seminal paper

to see how this may be diverted even for those who are undergoing

castration therapy(5).

Sam.

For your delectation and edification:-

http://poetryfromtheprostrateyears.com/

1. Anticancer Agents Med Chem. 2010 Mar;10(3):213-24. The vitamin

D/CYP24A1 story in cancer. King AN, Beer DG, Christensen PJ, Simpson

RU, Ramnath N. Department of Medicine, University of Michigan, 1500

East Medical Center Drive, Ann Arbor, MI 48109, USA.

There is increasing evidence linking the incidence of certain cancers

to low serum Vitamin D levels. The active metabolite of Vitamin D,

calcitriol (1, 25-Dihydroxyvitamin D(3), 1,25(OH)(2)D(3)) apart from a

crucial role in maintaining mineral homeostasis and skeletal

functions, has antiproliferative, apoptosis and differentiation

inducing as well as immunomodulatory effects in cancer. In studying

the role of 1,25(OH)(2)D(3) in cancer, it is imperative to examine the

potential pathways that control local tissue levels of

1,25(OH)(2)D(3).

The enzyme CYP24A1 or 24-hydroxylase converts 1,25(OH)(2)D(3) to

inactive calcitroic acid. Extra-renal production of this enzyme is

observed and has been increasingly recognized as present in cancer

cells. This enzyme is rate limiting for the amount of local

1,25(OH)(2)D(3) in cancer tissues and elevated expression is

associated with an adverse prognosis. The gene that encodes CYP24A1

has been reported as an oncogene and may contribute to tumor

aggressiveness by abrogating local anti-cancer effects of

1,25(OH)(2)D(3).

It is imperative to study the regulation of CYP24A1 in cancer and

especially the local metabolism of 1,25(OH)(2)D(3) in cancer cells.

CYP24A1 may be a predictive marker of 1,25(OH)(2)D(3) efficacy in

patients with cancer as an adjunctive therapy. The following review

summarizes the available literature on CYP24A1 as it relates to

1,25(OH)(2)D(3) in cancer and outlines potential ways to inhibit

CYP24A1 in an effort to improve the efficacy of exogenous

1,25(OH)(2)D(3). PMID: 20184548

http://www.ncbi.nlm.nih.gov/pubmed/20184548

2. Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13589-94. An endocrine

pathway in the prostate, ERbeta, AR,

5alpha-androstane-3beta,17beta-diol, and CYP7B1, regulates prostate

growth. Weihua Z, Lathe R, Warner M, Gustafsson JA. Department of

Medical Nutrition, Karolinska Institute, Novum, S-141 86 Huddinge,

Sweden. Erratum in: Proc Natl Acad Sci U S A. 2006 May

23;103(21):8298.

Epithelial proliferation of the ventral prostate in rodents peaks

between 2 and 4 weeks of age, and by week 8, proliferating cells are

rare. We have used ERbeta(-/-) and CYP7B1(-/-) mice to investigate the

role of ERbeta and one of its ligands,

5alpha-androstane-3beta,17beta-diol (3betaAdiol), in growth of the

ventral prostate. Before puberty, ERbeta was found in quiescent but

not in proliferating cells, and proliferating cells occurred more

frequently in ventral prostates of ERbeta(-/-) mice than in wild-type

littermates. Treatment with 3betaAdiol decreased proliferation in

wild-type but not in ERbeta(-/-) mice. In rats, treatment with

3betaAdiol from postnatal day 2 to 28 resulted in reduction in growth

of ventral prostates.

The prostates of CYP7B1(-/-) mice were hypoproliferative before

puberty and smaller than those of their wild-type littermates after

puberty. Because CYP7B1 represents the major pathway for inactivating

3betaAdiol in the prostate, we suggest that ERbeta, 3betaAdiol, and

CYP7B1 are the components of a pathway that regulates growth of the

rodent ventral prostate. In this pathway, ERbeta is an

antiproliferative receptor, 3betaAdiol is an ERbeta ligand, and CYP7B1

is the enzyme that regulates ERbeta function by regulating the level

of 3betaAdiol. PMCID: PMC129718 PMID: 12370428

http://www.ncbi.nlm.nih.gov/pubmed/12370428

3. Prostate. 2007 Sep 15;67(13):1439-46. Regulation and expression of

human CYP7B1 in prostate: overexpression of CYP7B1 during progression

of prostatic adenocarcinoma. Olsson M, Gustafsson O, Skogastierna C,

Tolf A, Rietz BD, Morfin R, Rane A, Ekström L. Department of Urology,

Karolinska Institutet, Karolinska University Hospital, Stockholm,

Sweden.

BACKGROUND: Cytochrome P450 (CYP) 7B1 is involved in many metabolic

processes including androgen metabolism. Cytochrome P450 (CYP) 7B1 is

expressed within the prostate and may determine the levels of the

natural estrogen receptor beta (ERbeta) ligand

5alpha-androstane-3beta,17beta-diol (3betaAdiol) available and hence

affect the regulation of prostate proliferation. We hypothesized that

CYP7B1 expression is increased in prostate tumors and that promoter

methylation contributes to the regulation of CYP7B1 expression in

human prostate tissue.

METHODS: Expression of the CYP7B1 gene and protein in clinical

prostate tissues and prostate cancer cell lines were investigated

using real-time PCR and immunohistochemistry. The methylation status

of the CYP7B1 gene was analyzed using methylation-specific PCR (MSP).

RESULTS: The immunohistochemical results demonstrate that high

expression of CYP7B1 protein occurs in high-grade prostatic

intraepithelial neoplasia (PIN) and adenocarcinomas. The ERbeta/CYP7B1

mRNA ratio was significantly lower in tumor compared to the non-tumor

area. The MSP analysis indicate that local methylation of CYP7B1

promoter region is an important mechanism involved in down-regulation

of CYP7B1 in human prostate tissue.

CONCLUSIONS: This is the first report showing that CYP7B1 is

overexpressed in high-grade PIN and in prostate cancer and that local

methylation of CYP7B1 promoter region may have significant effect on

gene transcription. PMID: 17639508

http://www.ncbi.nlm.nih.gov/pubmed/17639508

4. Pharmacogenomics J. 2004;4(4):245-50. A functional C-G polymorphism

in the CYP7B1 promoter region and its different distribution in

Orientals and Caucasians. Jakobsson J, Karypidis H, Johansson JE, Roh

HK, Rane A, Ekström L. Department of Laboratory Medicine, Division of

Clinical Pharmacology, Karolinska Institutet, Huddinge University

Hospital, Stockholm, Sweden. jenny.jakobsson@...

Cytochrome P450 (CYP) 7B1 is involved in many metabolic processes

including androgen metabolism. Genetic variation in the CYP7B1 gene

may play a role in predisposition to prostate cancer. Here, we

screened the human CYP7B1 gene for possible polymorphisms. Only one

single polymorphism was detected, a C-G change in the promoter -104

base pair from the transcription start site. The allele frequency was

investigated in Swedish men and compared to a Korean population, as it

is known that the frequency of prostate cancer is low among Orientals.

We found that the frequency of the G-allele was 4.04% in Swedes

(n=150) but only 0.33% among Koreans (n=153). Computer analysis

indicated that the two variants bind with different affinities to a

CCAAT-box binding protein. Expression studies with reporter constructs

showed significantly higher transcriptional activity of the G variant

in Hek293 cells (2.7-fold, P<0.05).

In conclusion, we report here for the first time the detection of a

single polymorphism in the CYP7B1 gene. This polymorphism is

associated with phenotypic differences in an expression system and a

widely different allele frequency in two ethnic populations, with

great differences in the incidence of prostate cancer. PMID: 15007371

http://www.ncbi.nlm.nih.gov/pubmed/15007371

5. Nucl Recept Signal. 2008 Feb 1;6:e003. Estrogen receptor beta: an

overview and update. Zhao C, Dahlman- K, Gustafsson JA.

Department of Biosciences and Nutrition, Novum, Karolinska Institutet,

Huddinge, Sweden. chunyan.zhao@...

The discovery of a second estrogen receptor (ER), designated ERbeta

(NR3A2), has redefined our knowledge about the mechanisms underlying

cellular signaling by estrogens and has broad implications for our

understanding of regulation of estrogen-responsive tissues. Highly

variable and even contrasting effects of estrogens in different

tissues seem to be at least partially explained by different estrogen

signaling pathways, involving ERalpha (NR3A1) and/or ERbeta. To date,

two key conclusions can be drawn from the significant body of work

carried out on the specific roles of the two receptor subtypes in

diverse estrogen target tissues.

First, ERalpha and ERbeta have different biological functions, as

indicated by their specific expression patterns and the distinct

phenotypes observed in ERalpha and ERbeta knockout (alphaERKO and

betaERKO) mice. Second, ERalpha and ERbeta appear to have overlapping

but also unique sets of downstream target genes, as judged from a set

of microarray experiments. Thus, ERalpha and ERbeta have different

transcriptional activities in certain ligand, cell-type, and promoter

contexts, which may help to explain some of the major differences in

their tissue-specific biological actions. The phenotypes observed for

betaERKO mice have suggested certain therapeutic areas to be further

explored.

The development of ERbeta-selective ligands active in animal disease

models indicates new avenues for clinical exploration. ERbeta agonists

are being explored and validated as drugs for a growing number of

indications. Hopefully, some ERbeta targeted drugs will prove to be

efficient in enhancing human health. PMCID: PMC2254331 PMID: 18301783

http://www.ncbi.nlm.nih.gov/pubmed/18301783

Key words:

SUBVERSION Subversion subversion