Cholesterol synthesis was demonstrated to be mandatory for cellular growth and serves to supply one of the necessary building blocks for new membranes demanded by dividing cells during growth. The
mevalonate pathway, which is regulated through a finely tuned mechanism, is responsible mainly for
cholesterol enrichment to cells. Among the various steps, the production of
mevalonate from 3-hydroxy-3-methylglutaryl
coenzyme A (
HMG-CoA) is the most critically regulated step catalyzed by
HMG-CoA reductase. The ability of
sterols to regulate both the transcriptional rates of the
reductase gene and the degradative machinery for the
reductase protein provides a multilevel system for controlling the expression of this
enzyme. Much convincing evidence indicates that cells manifest a higher flux through the
mevalonate pathway when proliferating than when they are in the cell cycle arrest condition; furthermore,
tumors undergo deregulated cholesterogenesis mainly at the critical rate-controlling juncture (i.e., the reaction catalyzed by
HMG-CoA reductase). The
mevalonate component of the
cholesterol biosynthesis plays a key role in controlling cell proliferation by generating
prenyl intermediates, particularly farnesyl and geranyl-geranyl moieties. These
isoprenoids covalently modify and thus modulate the
biological activity of signal transducing
proteins, such as that of the Ras superfamily. The prenylated Ras-mediated signal transduction pathway provides much of the molecular information needed to trigger cell proliferation. Therefore, depletion of
mevalonate can block both the processing and the transforming activities of Ras, indicating that drugs such as
lovastatin and
compactin, which had previously been exploited for lowering
cholesterol levels, may be useful chemotherapeutic agents for treating
tumors harboring oncogenic Ras mutation. In addition, Ras prenylation, which provides much of the molecular information needed to trigger cell proliferation, represents an inviting target for the design of chemotherapeutic drugs that would interrupt such signaling events and arrest
tumor cell proliferation.