Molecular Regulation of Cholesterol Biosynthesis: Implications in Carcinogenesis

Abstract

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.

Genome Expression Profiling-Based Identification and Administration Efficacy of Host-Directed Antimicrobial Drugs against Respiratory Infection by Nontypeable Haemophilus influenzae

“…Gene clustering network created by the IPA software showed intermolecular connections for HMGCR (see Fig. S2D in the supplemental material), the rate-controlling enzyme of the mevalonate pathway, which produces cholesterol and other isoprenoids (50). We showed previously that cholesterol is a component of the host membrane lipid rafts important for NTHi epithelial invasion (14).…”

Autocrine activation of an osteopontin-CD44-Rac pathway enhances invasion and transformation by H-RasV12

“…Osteopontin-CD44-Rac autocrine pathway in NIH3T3 cells H Teramoto et al mevalonate are required for the isoprenylation of Ras, and treatment of NIH3T3 cells with the HMG-CoA reductase inhibitor lovastatin depletes cells of mevalonate which impairs isoprenylation of Ras (Ownby and Hohl, 2002), a process known to inhibit cell proliferation (Singh et al, 2003). Hence, OPN may function to repress Insig-1 expression thereby facilitating cellular transformation, while OPN knockdown results in derepression and consequential inhibition of transforming activity as defined by focus formation.…”

Induction of cytotoxicity in human lung adenocarcinoma cells by 6‐O‐carboxypropyl‐α‐tocotrienol, a redox‐silent derivative of α‐tocotrienol

“…6,7 In general, tumors undergo deregulated cholesterogenesis mainly via the upregulation of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, a key enzyme of cholesterol synthesis. 8 HMG-CoA reductase plays a key role in controlling cell proliferation by generating prenyl intermediates, particularly farnesyl and geranyl-geranyl moieties, 8 so the upregulation of the enzyme in tumors finally stimulates the cell proliferation via the increase of prenylation in Ras molecules. Thus, agents such as lovastin, which had been exploited previously for lowering cholesterol based on the inhibition of HMG-CoA reductase, may be useful chemotherapeutic agents for treating tumors harboring oncogenic ras mutation.…”

“…Thus, agents such as lovastin, which had been exploited previously for lowering cholesterol based on the inhibition of HMG-CoA reductase, may be useful chemotherapeutic agents for treating tumors harboring oncogenic ras mutation. 8 Natural constituents such as sundry mevalonate-derived constituents (isoprenoids) of fruits, vegetables and cereal grains suppress the development of tumors, 9 and the suppressive effect mainly depends on limiting the posttranslational processing of growth-associated proteins such as the farnesylation of Ras protein through the suppression of HMG-CoA reductase. 10 Tocotrienols belong to a phytochemical class of isoprenoid molecules and are known as mixed isoprenoids.…”