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".
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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."
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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."
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I should mention here that:
"Inhibitors of squalene epoxidase have found application mainly as antifungal drugs:
- butenafine
- naftifine
- terbinafine"
(from Wikipedia [5])
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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...
