Squalene Synthase, a Determinant of Raft-associated Cholesterol and Modulator of Cancer Cell Proliferation

Abstract

Several cues for cell proliferation, migration, and survival are transmitted through lipid rafts, membrane microdomains enriched in sphingolipids and cholesterol. Cells obtain cholesterol from the circulation but can also synthesize cholesterol de novo through the mevalonate/isoprenoid pathway. This pathway, however, has several branches and also produces non-sterol isoprenoids. Squalene synthase (SQS) is the enzyme that determines the switch toward sterol biosynthesis. Here we demonstrate that in prostate cancer cells SQS expression is enhanced by androgens, channeling intermediates of the mevalonate/isoprenoid pathway toward cholesterol synthesis. Interestingly, the resulting increase in de novo synthesis of cholesterol mainly affects the cholesterol content of lipid rafts, while leaving non-raft cholesterol levels unaffected. Conversely, RNA interference-mediated SQS inhibition results in a decrease of raft-associated cholesterol. These data show that SQS activity and de novo cholesterol synthesis are determinants of membrane microdomain-associated cholesterol in cancer cells. Remarkably, SQS knock down also attenuates proliferation and induces death of prostate cancer cells. Similar effects are observed when cancer cells are treated with the chemical SQS inhibitor zaragozic acid A. Importantly, although the anti-tumor effect of statins has previously been attributed to inhibition of protein isoprenylation, the present study shows that specific inhibition of the cholesterol biosynthesis branch of the mevalonate/isoprenoid pathway also induces cancer cell death. These findings significantly underscore the importance of de novo cholesterol synthesis for cancer cell biology and suggest that SQS is a potential novel target for antineoplastic intervention.

Role of squalene synthase in prostate cancer risk and the biological aggressiveness of human prostate cancer

“…16 In the present study, we confirmed that FDFT1 expression levels were significantly reduced after 6 months of androgen deprivation therapy in human prostate specimens. Further studies are warranted to confirm the androgen dependency of squalene synthase in the human prostate gland.…”

“…15 A previous study showed that FDFT1 is expressed in human prostate cancer cells, that is, LNCaP cells. 16 We also reported FDFT1 expression in PC-3 and LNCaP cells. 17 To our knowledge, the association between FDFT1 genetic polymorphisms and prostate cancer has not been studied.…”

“…28,29 Thus, squalene synthase plays a key role in directing intermediates to the sterol branch of this metabolic pathway. Brusselmans et al 16 reported that squalene synthase regulates cellular levels of cholesterol. Cholesterol is known to be important in cancer cell growth, including prostate cancer.…”

ATP Citrate Lyase Knockdown Induces Growth Arrest and Apoptosis through Different Cell- and Environment-Dependent Mechanisms

“…De novo cholesterol synthesis is also shown to be elevated in cancer cells (10). Cholesterol is reported to be required for the growth of cancer cells (10,15). In addition, FPP can also be converted into geranylgeranyl pyrophosphate (GGPP; ref.…”

“…ACLY converts citrate into acetyl-CoA, a precursor for fatty acid and mevalonate synthesis pathways (6)(7)(8). Both of these pathways are associated with cancer cell growth and transformation (9)(10)(11).…”