"... AR-mediated lipid biosynthesis is highly conserved and reactivated during the progression to CRPC, and increased level of lipid synthesis is associated with poor prognosis. The restoration of lipid biosynthetic pathways is partially due to the increased expression of AR splice variants. Blocking lipid/cholesterol synthesis in AR variants-expressing CRPC cell line and xenograft models markedly reduces tumor growth through inhibition of mTOR pathway."
Adaptation to ADT (i.e. CRPC) involves learning to survive at lower androgen levels, but also synthesizing steroid hormones, for which cholesterol is required. & so "Blocking ... cholesterol synthesis" is very sensible. Which is why doctors should offer statins to men on ADT, IMO.
In another paper this year [2], silibinin, one of the polyphenols found in milk thistle, inhibited lipogenesis in PCa cells.
When cells in a tumor have reduced access to oxygen (hypoxia) we get HIF-1α expression (hypoxia-inducible factor 1alpha). But HIF-1α can be expressed when cells are having survival issues for other reasons.
"Interestingly, hypoxia promoted a lipogenic phenotype in PCa cells via activating acetyl-Co A carboxylase (ACC) and fatty acid synthase (FASN) that was inhibited by silibinin treatment."
Patrick, you seem to be a fountain of deep technical knowledge, your hard work is appreciated.
In regard to biosynthesis I have read that Metfomin may play a role in reducing cholesterol which refractory PC may use to create testosterone when it is eliminated through ADT/ androgen deprivation.
I have had the surgery and PSA was 3.3 and rose to 12 then Estogen patches has taken it down to 1.6 and still going down. I managed to get my clinical oncologist to prescribe Meformin for it's multiple benefits identified in oncology journals. Started six weeks of radiation and hoping that combined with Metformin and Estrodial will keep the wolf at bay.
When I was diagnosed 13 years ago I came across newly diagnosed men who were enthusiastic about this or that cancer "cure" that they were about to embark on. I suggested that they pay attention to the 10-year survivors in the group. When I reached the 10 year mark, I realized that I didn't have the answers. I was uncertain about being able to get to 15 years.
But perhaps I am around because of the small things I did. I obtained a prescription for Simvastatin. My GP rejected my request for Metformin, but my integrative medicine doctor had no problem with it. I also addressed inflammation, which has a negative survival impact, even in the absence of clinical disease. And I belatedly added nattokinase, to eliminate the metastatic potential of micro-clots. It must all sound boring to those expecting great insights.
Metformin doesn't seem like a strange request anymore. I knew that there seemed to be benefit in other cancers, but I was specifically interested if its effect on insulin sensitivity. It didn't matter to me that there might be other benefits.
Looking at the bigger picture, though, Metformin is an AMPK activator. It might be enought to know that AMPK activation is inhibited in PCa, but here is what it does:
"... stimulation of hepatic fatty acid oxidation, ketogenesis, stimulation of skeletal muscle fatty acid oxidation and glucose uptake, inhibition of cholesterol synthesis, lipogenesis, and triglyceride synthesis, inhibition of adipocyte lipolysis and lipogenesis, and modulation of insulin secretion by pancreatic beta-cells." [1]
Regarding cholesterol:
[2] "We found significantly lower ... concentrations of three metabolites (acyl-alkyl phosphatidylcholines [PCs]) when comparing mt-T2D {Metformin treated type 2 diabetes} with four control groups who were not using glucose-lowering oral medication. ... Furthermore, we observed that the levels of these metabolites decreased significantly in patients after they started metformin treatment during 7 years' follow-up. The reduction of these metabolites was also associated with a lowered blood level of LDL cholesterol (LDL-C)."
[3] "Compared with the placebo, metformin treatment also have a significant effect on reducing weight, body mass index, insulin, insulin resistance index, total cholesterol and triglyceride, and increasing high-density lipoprotein cholesterol."
[4] "Triglycerides (TG) were reduced in both groups .., but total cholesterol (TC) and low-density lipoprotein (LDL) were decreased only after metformin treatment"
[5] "Metformin safely and effectively reduces CHD risk factors (weight, fasting insulin, leptin, LDL cholesterol, centripetal obesity) in morbidly obese, nondiabetic subjects with BMI > 30, probably by virtue of its insulin-sensitizing action."
I use 2,000mg Metformin/day, but I wouldn't stop Simvastatin.
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CRPC - causes and prevention of 
Invitro study. Our novel findings indicate that safe doses of may be used to decrease AR expression and metastatic ability in CRPC cells
