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Cholesterol in high-grade and lethal PCa.

pjoshea13 profile image
5 Replies

New study below.

I was never a fan of statins. My GP offered me one when my total cholesterol went above 200. It seemed absurd that more that half the U.S. population of my age was using statins, when prudent dietary changes might remove excess CVD risk without the need for a drug.

But cancer is different than CVD. A hundred years ago it was noted that solid tumors accumulated cholesterol. Much, much later, it was reported that higher levels of cholesterol in PCa cells were associated with poorer outcomes.

When I was diagnosed it was thought that ADT failed when cells no longer needed testosterone. Now we know that most CRPC cells still rely on the androgen receptor [AR], & except in the case of splice variants, such as AR-V7, this requires androgen. If forced to, PCa cells will create androgen from cholesterol - & will even first synthesise cholesterol. & so I have been using 40 mg Simvastatin for ~7-8 years.

The new study involves men in the "Physicians' Health Study, and the Swedish Watchful Waiting Study".

Note: "LDRL" refers, I believe, to the receptor for low density lipoprotein. LDL can transport cholesterol [LDL-C], & prostatic LDLR is involved in the uptake of LDL-C. Dr. Myers has said that smaller LDL particles are a particular problem & that we should pay attention to our VLDL-C levels. However:

"... cancers that became lethal despite primary treatment were characterized by low LDLR expression ..."

Seemingly, they no longer relied so much on circulating cholesterol as they became aggressive.

Note: "SOAT1" is one of the isoforms of Sterol O-acyltransferase which form cholesteryl esters from cholesterol. [3]

Note: SQLE is squalene monooxygenase [2]. It "catalyzes the first oxygenation step in sterol biosynthesis and is thought to be one of the rate-limiting enzymes in this pathway"

"Higher Gleason grade was associated with ... lower SOAT1 and higher SQLE expression."

"... prostate cancers that progress to lethal disease rely on de-novo cholesterol synthesis (via SQLE), rather than transcellular uptake (via LDLR) or cholesterol esterification (via SOAT1)."

Statins inhibit HMG-CoA reductase, which is involved in cholesterol synthesis. For those who really want to know how everything fits together, see the chart below.

But the bottom line is that cholesterol is an extremely important target. More important than I realized 8 years ago. The importance of a statin in PCa was never so much about reducing circulating LDL-C, but in inhibiting synthesis within the cells. In fact, circulating levels seem to be increasingly irrelevant with progression.

Note that men with low LDL-C probably think that they do not need a statin, but IMO they are particularly at risk for PCa cholesterol neogenesis.

Dr. Mercola seems to have some men more worried of statins than ADT [LOL], but, in my view, a statin is an essential add-on to Zytiga.

-Patrick

Note: [2]

"Inhibitors of squalene epoxidase have found application mainly as antifungal drugs:

butenafine

naftifine

terbinafine"

Perhaps they would be useful off-label in PCa.

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/285...

Carcinogenesis. 2017 Jun 8. doi: 10.1093/carcin/bgx058. [Epub ahead of print]

Cholesterol uptake and regulation in high-grade and lethal prostate cancers.

Stopsack KH1, Gerke TA2, Andrén O3, Andersson SO3, Giovannucci EL4,5,6, Mucci LA4,5, Rider JR4,7.

Author information

1

Department of Internal Medicine, Mayo Clinic, Rochester, MN.

2

Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL.

3

Department of Urology, School of Health and Medical Sciences, University of Örebro, Örebro, Sweden.

4

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA.

5

Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

6

Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA.

7

Department of Epidemiology, Boston University School of Public Health, Boston, MA.

Abstract

Lethal prostate cancers have higher expression of squalene monooxygenase (SQLE), the second rate-limiting enzyme of cholesterol synthesis. Preclinical studies suggested that aberrant cholesterol regulators, receptors, and transporters contribute to cholesterol accumulation uniformly. We assessed their association with features of aggressive cancers. In the prospective prostate cancer cohorts within the Health Professional Follow-up Study, the Physicians' Health Study, and the Swedish Watchful Waiting Study, tumor mRNA expression profiling was performed. Lethal disease was defined as mortality or metastases from prostate cancer (n = 266) in contrast to non-lethal disease without metastases after >8 years of follow up (n = 476). Associations with Gleason grade were additionally assessed using The Cancer Genome Atlas primary prostate cancer dataset (n = 333). Higher Gleason grade was associated with lower LDLR expression, lower SOAT1, and higher SQLE expression. Besides high SQLE expression, cancers that became lethal despite primary treatment were characterized by low LDLR expression (odds ratio for highest vs. lowest quintile, 0.37; 95% CI, 0.18 to 0.76) and by low SOAT1 expression (odds ratio, 0.41; 95% CI, 0.21 to 0.83). The association of LDLR expression and lethality was not present in tumors with high IDOL expression. ABCA1, PCSK9, or SCARB1 expressions were not associated with Gleason grade or lethal cancer. In summary, prostate cancers that progress to lethal disease rely on de-novo cholesterol synthesis (via SQLE), rather than transcellular uptake (via LDLR) or cholesterol esterification (via SOAT1). These results may help design pharmacotherapy for high-risk patients.

© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

KEYWORDS:

IDOL; LDLR; SOAT1; cholesterol; prostate cancer

PMID: 28595267 DOI: 10.1093/carcin/bgx058

[2] en.wikipedia.org/wiki/Squal...

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

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

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pjoshea13 profile image
pjoshea13

Apologies for the missing chart - it was there when I posted.

Here is the link:

wikipathways.org/index.php/...

-Patrick

BigRich profile image
BigRich

Patrick,

You are correct regarding dietary modification; my cholestrol score went from 256 to 150.

Rich

Neal-Snyder profile image
Neal-Snyder in reply toBigRich

But that doesn't work if the problem is hereditary. Long before my PCa, I was eating healthy & playing basketball daily, but I had to start on a statin. Similar story for my sister.

erjlg3 profile image
erjlg3

Very interesting pjoshea13. Thank you for posting. Elgie uses Ursadiol for cholesterol because of the side effects of statins. Dr. Charles Myers prescribed it. He has done well on it but we were discussing him not taking it recently due to possibly not needing it.

:) Jackie

So, we have two corroborating points of view. I did what Rich did, adjusted my diet. But, that was after my Primary Doc took me off the statin I was using. I then again adjusted my diet back to a, "who cares, I'll eat what I want" diet, and my cholesterol is normal. Don't ask, I have no clue.

Joe

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