Modulation of mammary cancer cell migration by 15-deoxy-Δ12,14-prostaglandin J2: implications for anti-metastatic therapy

Abstract

SYNOPSIS Recently, a number of steps in the progression of metastatic disease have been shown to be regulated by redox signaling. Electrophilic lipids affect redox signaling through the post-translational modification of critical cysteine residues in proteins. However, the therapeutic potential as well as the precise mechanisms of action of electrophilic lipids in cancer cells is poorly understood. In this study, we investigate the effect of the electrophilic prostaglandin 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) on metastatic properties of breast cancer cells. 15d-PGJ2 was shown to decrease migration, stimulate focal adhesion disassembly and cause extensive F-actin reorganization at low concentrations (0.03-0.3 μM). Importantly, these effects seem to be independent of PPARγ and modification of actin or Keap1, which are known protein targets of 15d-PGJ2 at higher concentrations. Interestingly, the p38 inhibitor SB203580 was able to prevent both 15d-PGJ2-induced F-actin reorganization and focal adhesion disassembly. Taken together, our results suggest that electrophiles such as 15d-PGJ2 are potential anti-metastatic agents which exhibit specificity for migration and adhesion pathways at low concentrations where there are no observed effects on Keap1 or cytotoxicity.

TGF-β1 Downregulates COX-2 Expression Leading to Decrease of PGE2 Production in Human Lung Cancer A549 Cells, Which Is Involved in Fibrotic Response to TGF-β1

“…PGD2 and its metabolite 15-deoxy-D 12,14 PGJ2 (15d-PGJ2) have been reported to induce apoptosis in A549 cells, human cervical cancer cells and human leukemia cells [51,52]. PGD2 also inhibits TGF-β1-induced EMT in MDCK cells, and 15d-PGJ2 decreases the metastatic potential of breast cancer cells [53,54]. Therefore, TGF-β1-induced COX-2 suppression might be expected to promote cancer progression.…”

Tumor Invasion and Oxidative Stress: Biomarkers and Therapeutic Strategies

“…One such redox signaling molecule is the electrophilic cyclopentenone prostaglandin 15d-PGJ2 (15-deoxy-12,14-prostaglandin J2), an inflammatory molecule, which can affect redox signaling through the posttranslational modification of critical cysteine residues in proteins such as actin, vimentin, and tubulin [40]. 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 [39].…”

“…It is thus becoming clear that a number of steps in the metastatic cascade, such as invasion, intravasation, and extravasation, are regulated by redox signaling [39]. One such redox signaling molecule is the electrophilic cyclopentenone prostaglandin 15d-PGJ2 (15-deoxy-12,14-prostaglandin J2), an inflammatory molecule, which can affect redox signaling through the posttranslational modification of critical cysteine residues in proteins such as actin, vimentin, and tubulin [40].…”

Cyclooxygenases and lipoxygenases in cancer

“…Since 15d-PGJ 2 is considered an endogenous PPARgamma ligand [43], and activation of PPARgamma has been shown to have anti-tumorigenic activity [44], the role of PGJ 2 metabolites in modulation of tumor cell function has been investigated. Similarly to PGD 2 , 15d-PGJ 2 decreases migration and invasion of breast cancer cells [45], promotes colon cancer apoptosis [46], decreases the expression of the anti-apoptotic Bcl-2 in human hepatocellular carcinoma cells [47], and induces mitotic arrest by destabilizing microtubules [48]. Finally, the activation of PPARgamma by 15d-PGJ 2 reduces the transcription of the pro-tumorigenic thromboxane TPbeta receptor in erythroleukemial cells [49].…”