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.