Plant-derived isoprenoids mediate regulation of mTOR signaling in tumor cells

Abstract

It is widely recognized that metabolites derived from plants behave as preemptive nutrients that provide cytoprotection or modify disease risk through processes regulating gene expression at the levels of transcription, DNA methylation as well as formation or bioactivation of proteins. In contrast, lipid-related terpenes, commonly referred to as isoprenoids, are bioactive secondary products of plant mevalonate metabolism that modulate mammalian cell growth, survival, differentiation and autophagic cell death through their effects on gene expression at the level of mRNA translation via the mammalian target of rapamycin (mTOR) pathway. Early findings from our laboratory established that isoprenoids such as perillyl alcohol suppressed 3-hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme of mevalonate/cholesterol biosynthesis, through a mechanism regulating mRNA translational efficiency. Additionally, our studies found that perillyl alcohol suppressed 4E-BP1 phosphorylation in tumor cells via the mTOR pathway, and disrupted the m7GpppX mRNA cap binding complex, eIF4F, by suppressing interaction of eukaryotic initiation factor 4E (eIF4E) with eIF4G. Furthermore, isoprenoids exhibit certain rapamycin-like inhibitory effects on the rapamycin-sensitive mTORC1 complex, but also have distinct effects on the rapamycin-insensitive TSC1/2-mediated regulation of mTOR signaling. Overall, these effects on mTOR signaling suppress cap-dependent protein translation and set-up conditions for cap-independent translation that in part mediate isoprenoid-induced tumor cell death through a caspase-independent mechanism similar to autophagy. Additionally, other studies have reported that polyphenols, flavonoids and triterpenes induced cell death through a similar mechanism.