RT Journal Article
SR Electronic
T1 Mevalonate signaling, COPD and cancer: the statins and beyond
JF Journal of Investigative Medicine
JO J Investig Med
FD BMJ Publishing Group Ltd
SP 711
OP 714
DO 10.1136/jim-2018-000829
VO 67
IS 4
A1 Raewyn J Hopkins
A1 Robert P Young
YR 2019
UL http://hw-f5-jim.highwire.org/content/67/4/711.abstract
AB Evidence suggests that smoking confers a persistent and/or exaggerated inflammatory response in the lungs that, with underlying genetic susceptibility, may result in lung remodeling and impaired repair. The innate immune response to smoking described above, which is modified by the mevalonate pathway, provides a plausible pathogenic link between the development of chronic obstructive pulmonary disease and lung cancer. The mevalonate pathway modifies innate responsiveness through important intracellular signaling molecules called guanine phosphate transferases (GTPases) such as Rho-A. Smoke exposure activates cell surface proteins which, through the mediating influence of GTPases, then modifies the activation of nuclear factor kappa -light-chain-enhancer of activated B cells (NFĸB) its downstream effects on genes underlying innate immunity, neutrophilic inflammation and carcinogenesis. The mevalonate pathway is modifiable through the enzyme 3-hydroxy-3-methyl-glutaryl-Coenzyme A (HMGCo-A) reductase. This enzyme controls the rate limiting step of the mevalonate pathway and is subject to inhibition by statin drugs (HMGCo-A reductase inhibitors) and small chain fatty acids derived from high dietary fiber intake. Ths, inhibitory effect dampens the innate immune response to smoking and may modify pulmonary inflammation and lung remodeling. This article is a symposia summary outlining the preclinical and clinical data suggesting that statins and a high-fiber diet may have a chemopreventive effect on lung cancer.