Statins and Protein Prenylation in Cancer Cell Biology and Therapy

Abstract

The use of statins has scaled up to become one of the most prescribed medicines in the world and have been very useful in the manegement of cardiovascular diseases and related mortality. The disclosure of their chemical structure similar to that of hydroxy methyl glutaryl-CoA (HMG-CoA) revealed their ability to compete with and inhibit the rate-limiting enzyme HMG-CoA reductase that catalyzes the synthesis of mevalonate, which then serves as the precursor for isoprenoids and cholesterol in the mevalonate pathway. While most of the effects of statins are associated with the lowering of cellular cholesterol levels, it is clear that they also blunt the non-sterol branch of the mevalonate pathway, decreasing formation of isoprenoids and altering protein-prenylation, a critical event in the posttranslational modulation of proteins involved in the regulation of cell cycle progression, proliferation and signaling pathways. Randomized controlled trials for the prevention of cardiovascular diseases indicated that statins elicited provocative and unexpected benefits for reducing a number of different types of cancers, including colorectal carcinoma, melanoma, prostate and hepatocellular carcinoma, although in other cancer types the preclinical expectations of statins were dissapointing. In this review, we will describe the evidence and mechanisms underlying the potential beneficial use of statins and the role of protein prenylation in cancer prevention. Of relevance, the combination of statins with other anti cancer drugs may be a significant asset in malignancies resistant to current therapy.

Statins: A New Approach to Combat Temozolomide Chemoresistance in Glioblastoma

“…Mevalonate serves as the precursor of isoprenoids and cholesterol in this pathway 10. Statins block HMGCR-mediated production of isoprenoid pyrophosphates (farnesyl diphosphate (FPP) and geranylgeranyl diphosphate (GGPP)) 11.…”

Mechanisms of BK virus infection of renal cells and therapeutic implications

“…These data suggest that statins, acting via depletion of Cav-1, could prevent caveolar-dependent BKV entry and repress BKV infection of HRPTEC. Even though decrease of Cav-1 was demonstrated in pravastatin-treated HRPTEC [25], it must be taken into consideration that non-cholesterol mechanisms of statin action have been proposed[26]. Inhibition of the mevalonate pathway, which is inhibited by statins, also affects synthesis of isoprenoid precursors for prenylation of a number of signaling molecules, including Ras family of proteins[27].…”

Statins and risk of breast cancer recurrence.

“…1 Statins reduce cholesterol biosynthesis in the liver by interfering with the mevalonate pathway and inhibiting HMGCR. In addition to cholesterol, this pathway produces isoprenoids, which are necessary for regulation of cell growth and oncogene expression, [2][3][4][5][6][7][8][9] while cholesterol is a critical component of intracellular lipid rafts, which are pivotal for intracellular signaling. 9 Apart from their role as lipid-lowering agents, they have been found to have immunomodulatory and antineoplastic effects.…”