Title:Mevalonate Pathway and Human Cancers
Volume: 10
Author(s): Seyedeh Zahra Bathaie, Mahboobeh Ashrafi, Mahshid Azizian and Fuyuhiko Tamanoi
Affiliation:
Keywords:
Farnesyl pyrophosphate, geranylgeranyl pyrophosphate, HMG-CoA reductase, MVA dysregulation, MVA inhibitors,
SREBP, statins.
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.