Mevalonate Pathway and Human Cancers

Abstract

Mevalonate (MVA) is synthesized from 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) by HMG-CoA reductase (HMG-CoAR). MVA is further metabolized to farnesyl pyrophosphate (FPP), a precursor of cholesterol and sterols. FPP is also converted to geranylgeranyl pyrophosphate, and these lipids are used for post-translational modification of proteins that are involved in various aspects of tumor development and progression. Many studies showed that the MVA pathway is up-regulated in several cancers such as leukemia, lymphoma, multiple myeloma; as well as breast, hepatic, pancreatic, esophageal and prostate cancers. Several mechanisms may be involved in dysregulation of this pathway. They include p53 mutation, a mutation in HMG-CoAR and sterol-regulatory element binding protein (SREBP) cleavage-activating protein SCAP as its regulator, PKB/Akt activation, decreased AMPK activation, and activation of transcription factors such as: SREBP and HIF-1. Statins as inhibitors of MVA pathway might be useful for cancer prevention and/or treatment through their interactions with essential cellular functions, such as cell proliferation and differentiation. Other inhibitors are also designed for inhibition of this key pathway and their mechanism of action was investigated. In the present review, we will first describe about some inhibitors of MVA, including statins that have been suggested for cancer treatment. We will then discuss about the mechanisms involved in MVA dysregulation, especially in cancer.

PBA Preferentially Impairs Cell Survival of Glioblastomas Carrying mutp53 by Reducing Its Expression Level, Stabilizing wtp53, Downregulating the Mevalonate Kinase and Dysregulating UPR

“…The capacity to stabilize mutp53 has been confirmed in this study by the use of lovastatin that reduced mutp53 expression level in U373 cells (data not shown). The targeting of the mevalonate pathway is emerging as a promising strategy to counteract several diseases including cancer [18,23]. Of note, mevalonate is not the only pathway with which mutp53 establishes a criminal alliance to promote cancer cell survival/progression/chemoresistance [7,24]; therefore its downregulation by PBA may interfere with a variety of other oncogenic pathways.…”

Non-canonical functions of enzymes facilitate cross-talk between cell metabolic and regulatory pathways

“…These data indicate that mRNA-binding activity and the catalytic activity of MVK are mutually exclusive 98 , 105 . Considering the frequent deregulation of enzymes of the mevalonate pathway in various human cancers 109 , it will be interesting to see whether MVK might also interact with other mRNAs to modulate the expression of cancer-relevant genes.…”

Lipid metabolism reprogramming and its potential targets in cancer

“…Statins are inhibitors of HMG-CoA reductase and are widely used to reduce circulating cholesterol levels. The anti-cancer effects of statins have been tested for various types of cancers, both pre-clinically and in patients [ 140 , 142 , 143 , 145 ]. However, inhibition of cholesterol synthesis can lead to feedback activation of SREBPs, making the anti-cancer effects of statins less effective [ 144 ].…”