Squalene Monooxygenase

[pjoshea13]

New Australian study below [1].

When tumors outgrow their blood supply, they experience hypoxia (insufficient oxygen).  The normal defence for any cell is the generation of hypoxia-inducible factors [HIFs].  HIFs have cell survival functions.

In PCa, HIF-1alpha is the most studied.  It triggers the generation of new blood vessels (angiogenesis), and is associated with treatment resistance.  Normoxic PCa cells may jump the gun.  A nitroglycerine patch may delay hypoxia.

The new study reports that "Hypoxia ... activates the key cholesterol synthesis enzyme squalene monooxygenase".

***

PubMed has 7 other PCa studies for Squalene Monooxygenase, starting with a 2016 U.S./Swedish study [2].  (See also [3] from the same team.)

The paper begins with a reminder that "Cholesterol metabolism has been implicated in prostate cancer pathogenesis."

"We analyzed the prospective prostate cancer cohorts within the Health Professionals Follow-up Study (n = 249) and the Physicians' Health Study (n = 153) as well as expectantly managed patients in the Swedish Watchful Waiting Study (n = 338)."

"The expression of squalene monooxygenase (SQLE) was associated with lethal cancer in all three cohorts. ... 

"Men with high SQLE expression (>1 standard deviation above the mean) were 8.3 times ... more likely to have lethal cancer despite therapy compared with men with the mean level of SQLE expression. ... 

"Absolute SQLE expression was associated with lethal cancer independently from Gleason grade and stage, as was a SQLE expression ratio in tumor versus surrounding benign prostate tissue. ...

"Higher SQLE expression was tightly associated with increased histologic markers of angiogenesis."

***

A 2021 Chinese paper [4] reported that:

"Our study revealed that SQLE is involved in the progression of castration resistance in CRPC through mediating metabolic reprogramming, presenting SQLE as a new target for the treatment of mCRPC."

***

I should mention here that:

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

- butenafine

- naftifine

- terbinafine" 

(from Wikipedia [5])

***

Germany (2021) [6]:

"Here, we show that squalene epoxidase (SQLE), an enzyme of the cholesterol biosynthesis pathway, is overexpressed in advanced PCa and its expression correlates with poor survival. ...

"SQLE expression is controlled by micro-RNA 205 (miR-205), which is significantly downregulated in advanced PCa. Restoration of miR-205 expression or competitive inhibition of SQLE led to inhibition of de novo cholesterol biosynthesis. ...

"Furthermore, SQLE was essential for proliferation of AR-positive PCa cell lines, including abiraterone or enzalutamide resistant derivatives, and blocked transactivation of the AR pathway. ...

"Inhibition of SQLE with the FDA approved antifungal drug terbinafine also efficiently blocked orthotopic tumour growth in mice. ... 

"Finally, terbinafine reduced levels of prostate specific antigen (PSA) in three out of four late-stage PCa patients."

-Patrick

[1]  pubmed.ncbi.nlm.nih.gov/366...

[2]  pubmed.ncbi.nlm.nih.gov/273...

[3]  pubmed.ncbi.nlm.nih.gov/285...

[4]  pubmed.ncbi.nlm.nih.gov/343...

[5]  en.wikipedia.org/wiki/Squal...

[6]  pubmed.ncbi.nlm.nih.gov/344...

[cujoe]

Darn fine to see the old authentic pjoshea13 authorship back in use.

[softwaremom00]

Great post. I am a little confused. Do we want to inhibit squalene epoxidase? If yes any ideas on the antifungal drugs that do this? Love seeing your posts. Thank you for the great information now and in all of the posts that I have read by you in the past 6 years.

[pjoshea13 in reply to softwaremom00]

Yes, SQLE is a bad actor & needs to be controlled.

When I was writing about the antifungals, I was thinking that this was Nalakrats territory.  LOL

But Terbinfine is one to remember (must be oral):

"To the best of our knowledge, this retrospective cohort study is the first nationwide population-based study to explore whether use of terbinafine is associated with an improved prognosis in patients with prostate cancer. The main finding from our study is that patients with prostate cancer who received systemic use of terbinafine had a 47% decrease in prostate cancer mortality and a 36% decrease in overall mortality as compared to patients without use of terbinafine after consideration for a range of clinical and demographic factors. An improved prognosis in patients with systemic use of terbinafine was also observed in several sensitivity analyses.

"onlinelibrary.wiley.com/doi...

Another possibility?  Garlic - diallyl disulfide [DADS]:

pubmed.ncbi.nlm.nih.gov/113...

Best, -Patrick

[MateoBeach]

The SQLE down-regulation by Terbinfine is very interesting. And since it is a key step in cholesterol synthesis makes me curious about intersection with statins in that pathway.

But circling back to the nitroglycerin patch for reducing tumor hypoxia: Would that be solely for the arteriolar vasodilation? Or for its role as a nitric oxide precursor/promotor? This phase two study found it slowed PSADT from 13.3 to 31.8 months.

pubmed.ncbi.nlm.nih.gov/194...

[pjoshea13 in reply to MateoBeach]

Hi Paul,

(I didn't realize that I now have two names on FPC! Seems that some might not have made the connection with previous posts.).

The Siemens paper (2009) convinced me to get the nitro patch.

NO, of course, causes the dilation that might delay PCa hypoxia.

I didn't investigate beyond that.

Another long-time repurposed med: Simvastatin to target cholesterol generation in PCa cells.

-Patrick 

[cesces]

This hypoxia is why Dr. Myers originally put me on low dose 20mg Viagra.

[Graham49 in reply to cesces]

Yes, there is evidence that ed medications can help, see previous post.

PDE5 inhibitors eg Taladalfal etc. 2 papers, one a cohort study showing positive survival association. The second about invitro studies

Graham49

7 months ago•3 Replies

The association of phosphodiesterase-5 inhibitors with the biochemical recurrence-free and overall survival of patients with prostate cancer following radical prostatectomy