Guggulsterone induces heme oxygenase-1 expression through activation of Nrf2 in human mammary epithelial cells: PTEN as a putative target

Abstract

Guggulsterone (GS) [4,17(20)-pregnadiene-3,16-dione] is a phytosterol found in the gum resin of the Commiphora mukul. GS exists naturally in two stereoisomers: E-GS (cis-GS) and Z-GS (trans-GS). In this study, the effects of both isomers on expression of the cytoprotective enzyme heme oxygenase-1 (HO-1) were evaluated in human mammary epithelial (MCF10A) cells. NF-E2-related factor 2 (Nrf2) is considered a master regulator in activating antioxidant response element (ARE)-driven expression of HO-1 and many other antioxidant/cytoprotective proteins. cis-GS upregulated the transcription and protein expression of HO-1 to a greater extent than did trans-GS. cis-GS treatment enhanced nuclear translocation and ARE-binding activity of Nrf2. MCF10A cells transfected with an ARE luciferase construct exhibited significantly elevated Nrf2 transcriptional activity upon cis-GS treatment compared with cells transfected with the control vector. In addition, silencing of the Nrf2 gene abrogated cis-GS-induced expression of HO-1. Incubation of MCF10A cells with cis-GS increased phosphorylation of Akt. The pharmacological inhibition of phosphoinositide 3-kinase (PI3K), an upstream kinase responsible for Akt phosphorylation, abrogated cis-GS-induced Nrf2 nuclear translocation. Pretreatment with the thiol-reducing agents attenuated Akt phosphorylation, Nrf2 activation and HO-1 expression, suggesting that cis-GS may cause thiol modification of an upstream signaling modulator. Phosphatase and Tensin Homologue Deleted on Chromosome 10 (PTEN) is a negative regulator of the PI3K-Akt axis. The mutation in cysteine 124 present in the catalytic domain of PTEN abolished cis-GS-induced HO-1 expression as well as Akt phosphorylation. Whether this cysteine is a 'bona fide' target of cis-GS in its activation of Nrf2 needs additional investigation.

Multiple regulations of Keap1/Nrf2 system by dietary phytochemicals

“…As shown in Table , ERK can be phosphorylated by fruit and vegetable constituents, such as quercetin, sulforaphane/PEITC, diallyl sulfide, hydroxytyrosol, resveratrol, lycopene, luteolin, procyanidin B2, anthocyanins, hesperidin, and ferulic acid; by herb constituents, such as α‐iso‐cubebenol, schisandrin B, oleanolic acid, eupatilin, Aralia continentalis extract, rottlerin, acteoside, tanshinone IIA, celastrol, and red ginseng extract; by tea and spice constituents, such as EGCG, epicatechin, lindenenyl acetate; and by marine products, such as eckol and fucoxanthin. p38 MAPK is also activated by fruit and vegetable constituents, such as quercetin, sulforaphane, diallyl sulfide, carnosic acid, lycopene, procyanidin B2, fisetin, and sesamin/episesamin; by herb constituents, such as Aralia continentalis extract, ginkgo biloba extract, rottlerin, celastrol, and mollugin; by tea and coffee constituents, such as EGCG and kahweol; by spices, such as curcumin and piperine; and by marine product like fucoxanthin.…”

Chemical and Biological Mechanisms of Phytochemical Activation of NRF2 and Importance in Disease Prevention

“…It must be noted, however, that mere reduction of reactivity without adjustment of other factors is expected to result in a situation where the enhanced selectivity and reduced toxicity come at the expense of potency. Thus, of two stereoisomers of guggulsterone, a terpenoid that lacks any known toxicity, only the E -form displays moderate ARE induction [101], due to, presumably, a poor accessibility by nucleophiles of the trisubstituted α,β-unsaturated ketone furnished with a quaternary center as the α-carbon substituent. The relatively low toxicity of coffee furans, as compared to other furans, can also be explained by steric factors, if the operative electrophile is a conjugated epoxydiene formed directly from kahweol (Figure 7.3.C) or after oxidative processing of cafestol.…”

“…The PI3K/Akt pathway mediates carnosol-induced expression of the cytoprotective enzyme HO-1 in rat pheochromocytoma PC12 cells [138]. In addition, EGCG, guggulsterone and piceatannol activate expression of cytoprotective enzymes including HO-1 in the human mammary epithelial (MCF10A) cells in a PI3K/Akt–dependent manner [101, 139, 140]. EGCG activation of Nrf2 in BAECs is also PI3K/Akt dependent [89].…”

“…The phosphorylation of Nrf2 by GSK-3β leads to both cytoplasmic localization of Nrf2 [142], and Keap1-independent ubiquitination by the SCF/β-TrCP/Cul1 complex, leading to Nrf2 degradation [143]. A key cysteine residue, C124 in PTEN, a negative regulator of the PI3K/Akt axis [144], is directly modified by biotinylated CDDO in ARPE-19 cells [141], and the same cysteine is required for guggulsterone-induced Nrf2 accumulation in MCF10A cells [101]. Remaining to be demonstrated is whether the modification of PTEN C124 by electrophilic agents also inactivates GSK-3β, and this in turn leads to Nrf2 accumulation and Nrf2 nuclear localization.…”

Antidepressant effects of standardized extract of Commiphora mukul Engl. in olfactory bulbectomized rats

“…Guggulsterone (GS) [4,17(20)-pregnadiene-3,16-dione] is a major phytosterol of C. mukul gum resin that exists in two stereoisomers: E-GS (cis-GS) and Z-GS (trans-GS) (Almazari et al 2012). There is considerable scientific evidence showing gum guggul as a therapeutic agent (Shah et al 2012).…”