15-Deoxy-Δ^12,14-prostaglandin J₂ Inhibits Cell Migration on Renal Cell Carcinoma <i>via</i> Down-Regulation of Focal Adhesion Kinase Signaling

Abstract

Renal cell carcinoma (RCC) is one of the chemoresistant cancers. There is a pressing need to establish therapeutic approaches to prevent RCC proliferation and metastasis. The electrophilic 15-deoxy-Δ 12,14prostaglandin J 2 (15d-PGJ 2) is an endogenous anti-cancerous agent. Treatment with high concentrations of 15d-PGJ 2 is known to induce apoptosis of RCC cells, independent of the nuclear receptor, peroxisome proliferator-activated receptor-γ (PPARγ). In this study, we investigated the effects of 15d-PGJ 2 on the metastatic properties of RCC Caki-2 cells. The metastatic potential of RCC was evaluated by measuring the migratory ability of Caki-2 cells. Although treatment with low concentrations of 15d-PGJ 2 did not cause apoptosis, it did decrease the migration of Caki-2 cells in a concentration-dependent manner. PPARγ did not mediate the inhibitory effect of 15d-PGJ 2 on the migration of Caki-2 cells. Treatment with a low concentration of 15d-PGJ 2 resulted in disassembled focal adhesions and extensive filamentous actin reorganization. Furthermore, 15d-PGJ 2 significantly reduced phosphorylation of focal adhesion kinase (FAK). In conclusion, 15d-PGJ 2 attenuated the migratory ability of RCC, independent of PPARγ. Further, 15d-PGJ 2 appeared to suppress cell migration via inactivation of FAK and subsequent disassembly of focal adhesion. Our present study highlights the therapeutic potential of 15d-PGJ 2 for prevention of RCC metastasis.

Cyclopentenone Prostaglandins: Biologically Active Lipid Mediators Targeting Inflammation

“…Treatment with a low concentration of 15d-PGJ 2 disassembled focal adhesions, reduced focal adhesion kinase (FAK) phosphorylation, and caused extensive filamentous actin reorganization (Yamamoto et al, 2020). PPAR-γ did not mediate the inhibitory effect of 15d-PGJ 2 on the migration of Caki-2 cells and did not affect RCC metastasis (Yamamoto et al, 2020).…”

“…15d-PGJ 2 inhibits NF-κB and AP-1-mediated MMP-9 expression and invasion of MCF-7 breast cancer cells employing a heme oxygenase-1 (HO-1)-dependent mechanism (Jang et al, 2020). Treatment with a low concentration of 15d-PGJ 2 disassembled focal adhesions, reduced focal adhesion kinase (FAK) phosphorylation, and caused extensive filamentous actin reorganization (Yamamoto et al, 2020). PPAR-γ did not mediate the inhibitory effect of 15d-PGJ 2 on the migration of Caki-2 cells and did not affect RCC metastasis (Yamamoto et al, 2020).…”

“…Continued Disassembled focal adhesions, downregulation of FAK signaling Renal cell carcinoma (RCC) metastasisYamamoto et al, 2020 …”

Nitric Oxide and Electrophilic Cyclopentenone Prostaglandins in Redox signaling, Regulation of Cytoskeleton Dynamics and Intercellular Communication

“…However, the regulation exerted on leukocyte-endothelial interactions by NO and CyPG is not restricted to endothelial cells (Figure 2A). For instance, 15-dPGJ 2 abrogates ICAM-1 expression on endothelial cells in mesenteric vessels through an NO-dependent mechanism, but disturbs actin cytoskeleton rearrangements and migration in renal carcinoma cells and neutrophils likely through formation of adducts with actin (Aldini et al, 2007;Napimoga et al, 2008;Yamamoto et al, 2020). Similarly, S-nitrosylation, and S-glutathionylation of actin regulate adhesion to endothelial cells and migration of neutrophils by interfering with cytoskeleton dynamics.…”