Mitochondrial targeting of the electrophilic lipid 15-deoxy-Δ12,14prostaglandin J2 increases apoptotic efficacy via redox cell signalling mechanisms

Abstract

SYNPOSIS Prototypical electrophiles such as the lipid 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) are well recognized for their therapeutic potential. Electrophiles modify signaling proteins in both the cytosol and mitochondrion which results in diverse cellular responses including cytoprotective effects and, at high doses, cell death. These findings led us to the hypothesis that targeting electrophiles to specific compartments in the cell can be used to fine-tune their biological effects. To examine this, we synthesized a novel mitochondrially-targeted analog of 15d-PGJ2 (mito-15d-PGJ2) and tested its effects on redox cell signaling. Mito-15d-PGJ2 caused profound defects in mitochondrial bioenergetics and mitochondrial membrane depolarization when compared to 15d-PGJ2. We also found that mito-15d-PGJ2 modified different members of the electrophile responsive proteome, was more potent at initiating intrinsic apoptotic cell death and was less effective than 15d-PGJ2 at upregulating the expression of heme oxygenase-1 and glutathione. These data demonstrate the feasibility of modulating the biological effects of electrophiles by targeting the pharmacophore to mitochondria.

Acquisition of Temozolomide Chemoresistance in Gliomas Leads to Remodeling of Mitochondrial Electron Transport Chain

“…TMZ-resistant glioma cells through an adaptive remodeling of the ETC activities may have built a more efficient coupling and may have a greater ability to increase mitochondrial electron transport during conditions of bioenergetic demand. This property may confer a selective advantage during the progression of the tumor, in particular under nutrient and hypoxic conditions (21,43,(57)(58)(59)(60). Our data also indicate that FCCP-linked respiration relative to the basal levels (reserve capacity) is higher in TMZresistant glioma cells compared with TMZ-sensitive ones.…”

Hemin causes mitochondrial dysfunction in endothelial cells through promoting lipid peroxidation: the protective role of autophagy

“…We have previously used biotinylated lipids to monitor protein adduct formation with reactive lipid species in cells (14,25,61). To determine whether hemin induces the formation of reactive lipid species we used a biotin-tagged derivative of arachidonic acid (Bt-AA).…”

Oxidative Therapy Against Cancer

“…Recently, a number of steps in the progression of metastatic disease have been shown to be regulated by redox signaling (Diers et al, 2010). One such redox signaling molecule is the electrophilic cyclopentenone prostaglandin, 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), which can affect redox signaling through the posttranslational modification of critical cysteine residues in proteins such as actin, vimentin, and tubulin.…”

“…One such redox signaling molecule is the electrophilic cyclopentenone prostaglandin, 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), which can affect redox signaling through the posttranslational modification of critical cysteine residues in proteins such as actin, vimentin, and tubulin. The fact that 15d-PGJ2 can alter the cytoskeleton coincides with decreased migration and increased focal-adhesion disassembly, which might have important implications in the inhibition of metastatic processes such as invasion, intravasation, and extravasation (Diers et al, 2010).…”