Resveratrol Induces Growth Arrest and Apoptosis through Activation of FOXO Transcription Factors in Prostate Cancer Cells

Resveratrol, a naturally occurring phytopolyphenol compound, has attracted extensive interest in recent years because of its diverse pharmacological characteristics. Although resveratrol possesses chemopreventive properties against several cancers, the molecular mechanisms by which it inhibits cell growth and induces apoptosis have not been clearly understood. The present study was carried out to examine whether PI3K/AKT/FOXO pathway mediates the biological effects of resveratrol.Resveratrol inhibited the phosphorylation of PI3K, AKT and mTOR. Resveratrol, PI3K inhibitors (LY294002 and Wortmannin) and AKT inhibitor alone slightly induced apoptosis in LNCaP cells. These inhibitors further enhanced the apoptosis-inducing potential of resveratrol. Overexpression of wild-type PTEN slightly induced apoptosis. Wild type PTEN and PTEN-G129E enhanced resveratrol-induced apoptosis, whereas PTEN-G129R had no effect on proapoptotic effects of resveratrol. Furthermore, apoptosis-inducing potential of resveratrol was enhanced by dominant negative AKT, and inhibited by wild-type AKT and constitutively active AKT. Resveratrol has no effect on the expression of FKHR, FKHRL1 and AFX genes. The inhibition of FOXO phosphorylation by resveratrol resulted in its nuclear translocation, DNA binding and transcriptional activity. The inhibition of PI3K/AKT pathway induced FOXO transcriptional activity resulting in induction of Bim, TRAIL, p27/KIP1, DR4 and DR5, and inhibition of cyclin D1. Similarly, resveratrol-induced FOXO transcriptional activity was further enhanced when activation of PI3K/AKT pathway was blocked. Over-expression of phosphorylation deficient mutants of FOXO proteins (FOXO1-TM, FOXO3A-TM and FOXO4-TM) induced FOXO transcriptional activity, which was further enhanced by resveratrol. Inhibition of FOXO transcription factors by shRNA blocked resveratrol-induced upregulation of Bim, TRAIL, DR4, DR5, p27/KIP1 and apoptosis, and inhibition of cyclin D1 by resveratrol.These data suggest that FOXO transcription factors mediate anti-proliferative and pro-apoptotic effects of resveratrol, in part due to activation of extrinsic apoptosis pathway

Mantle metasomatism

Mantle metasomatism is a relatively recent concept introduced in the early 1970s when detailed studies of lithospheric mantle rock fragments (xenoliths), brought to the surface of in basaltic to kimberlitic magmas, became widespread. Two main types of metasomatism were defined: modal (or patent) metasomatism describes the introduction of new minerals; cryptic metasomatism describes changes in composition of pre-existing minerals without formation of new phases. A new type of metasomatism is introduced here, stealth metasomatism; this process involves the addition of new phases (e.g. garnet and/or clinopyroxene), but is a “deceptive” metasomatic process that adds phases indistinguishable mineralogically from common mantle peridotite phases. The recognition of stealth metasomatism reflects the increasing awareness of the importance of refertilisation by metasomatic fluid fronts in determining the composition of mantle domains. Tectonically exposed peridotite massifs provide an opportunity to study spatial relationships of metasomatic processes on a metre to kilometre scale. The nature of mantle fluids can be determined from the nature of fluid inclusions in mantle minerals and indirectly from changes in the chemical (especially trace-element) compositions of mantle minerals. Metasomatic fluids in off-craton regions cover a vast spectrum from silicate to carbonate magmas containing varying types and abundances of dissolved fluids and solutes including brines, C-O-H species and sulfur-bearing components. Fluid inclusions in diamond and deep xenoliths reveal the presence of high-density fluids with carbonatitic and hydro-silicic and/or saline-brine end-members. The deep cratonic xenolith data also reinforce the importance of highly mobile melts spanning the kimberlite-carbonatite spectrum and that may become immiscible with changing conditions. A critical conceptual advance in understanding Earth’s geodynamic behaviour is emerging from understanding the linkage between mantle metasomatism and the physical properties of mantle domains recorded by geophysical data. For example, metasomatic refertilisation of cratonic lithospheric mantle increases its density, lowers its seismic velocity and strongly affects its rheology. Introduction of heat-producing elements (U, Th, K) increases heat production, and the key to understanding electromagnetic signals from mantle domains may be closely related to fluid distribution and type (e.g. carbonatitic) and its residence in or between grains. The lithospheric mantle is a palimpsest recording the multiple fluid events that have affected each domain since it formed. These events, involving different fluids and compositions, have repeatedly overprinted variably depleted original mantle wall-rocks. This produces a complex, essentially ubiquitously metasomatised lithospheric mantle, heterogeneous on scales of microns to terranes and perhaps leaving little or no “primary” mantle wall-rock. Decoding this complex record by identifying significant episodes and processes is a key to reconstructing lithosphere evolution and the nature and origin of the volatile flux from the deep Earth through time.63 page(s