The significance of the cholesterol biosynthetic pathway in cell growth and carcinogenesis (review).
Cholesterol is widely distributed in the animal kingdom and occurs in all cell membranes. Even though the majority of body cholesterol is synthesized by the liver and secreted as circulating lipoproteins, all cells in the body have genomic information for cholesterol biosynthesis. Cholesterol biosynthesis is under feedback regulation, and the cellular and circulating cholesterol levels are tightly regulated at several points, such as the rate limiting enzyme 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase and farnesyl pyrophosphate synthetase and at the low density lipoprotein (LDL) receptor. The cholesterol content and the rate of cholesterol biosynthesis are elevated in proliferating normal tissues and tumors. Cholesterol biosynthesis happens much before DNA synthesis, and inhibiting cholesterol biosynthesis inhibits cell growth, suggesting a linkage between the cholesterol and DNA synthetic pathways. The exact nature of this linkage is not known. However, recent evidence that the farnesyl moiety in the cholesterol biosynthetic pathway is necessary for the activation of G-proteins, and of the ras oncoprotein P21 has provided a probable basis for understanding this linkage, through signal transduction pathways. Thus, farnesylation of G proteins and ras oncoprotein P21 underscores the importance of the cholesterol biosynthetic pathway in cell growth and carcinogenesis. During normal cell growth and differentiation, LDL acts as a negative growth regulator and growth factors as positive signals, the neoplastic cell achieving autocrine growth due to the activation of protooncogens. It is interesting to note that in several types of cancer, the ras gene is mutated; these mutations could increase GTP binding, and lead to an activated p21. The activation of p21 would then be aided by continuous farnesylation due to stimulation of the cholesterol biosynthetic pathway in tumors. The cholesterol biosynthetic pathway, and ras p21 could therefore be used as targets for chemoprevention of cancer.
Rao
K N
KN
Department of Pathology, University of Pittsburgh School of Medicine, PA 15261, USA.
D000818:Animals; D002455:Cell Division / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002784:Cholesterol / Q000096:biosynthesis*; D004122:Dimethylallyltranstransferase / Q000235:genetics / Q000378:metabolism; D004790:Enzyme Induction; D005246:Feedback; D019204:GTP-Binding Proteins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D017368:Protein Prenylation; D011499:Protein Processing, Post-Translational; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism
D011973:Receptors, LDL; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D004122:Dimethylallyltranstransferase; D019204:GTP-Binding Proteins; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)