Int J Med Sci 2012; 9(7):555-566. doi:10.7150/ijms.4455

Research Paper

Cytotoxicity of 15-Deoxy-Δ12,14-prostaglandin J2 through PPARγ-independent Pathway and the Involvement of the JNK and Akt Pathway in Renal Cell Carcinoma

Megumi Fujita1, Chiaki Tohji1, Yoko Honda1, Yasuhiro Yamamoto2, Tsutomu Nakamura2, Tatsurou Yagami2, Motohiro Yamamori1, Noboru Okamura1 ✉

1. Department of Clinical Pharmacy, School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women's University, 11-68 Koshien-kyuban-cho, Nishinomiya, Hyogo 663-8179, Japan;
2. Department of Pharmaceutical Health Care, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, 2-1 Kami-ohno 7-Chome, Himeji, Hyogo 670-8524, Japan.

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Fujita M, Tohji C, Honda Y, Yamamoto Y, Nakamura T, Yagami T, Yamamori M, Okamura N. Cytotoxicity of 15-Deoxy-Δ12,14-prostaglandin J2 through PPARγ-independent Pathway and the Involvement of the JNK and Akt Pathway in Renal Cell Carcinoma. Int J Med Sci 2012; 9(7):555-566. doi:10.7150/ijms.4455. Available from

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Introduction: Agonists of peroxisome proliferator-activated receptor gamma (PPARγ) have been examined as chemopreventive and chemotherapeutic agents. The aim was to investigate the cytotoxicity and action mechanisms of 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), one of endogenous ligands for PPARγ, in terms of PPARγ-dependency and the mitogen-activated protein kinase (MAPK) and Akt pathway in three human renal cell carcinoma (RCC)-derived cell lines.

Methods: 786-O, Caki-2 and ACHN cells were used as human RCC-derived cell lines. Cell viability and caspase-3 activity was detected by fluorescent reagents, and chromatin-condensation was observed with a brightfield fluorescent microscope after staining cells with Hoechst33342. The expression levels of proteins were detected by Western blot analysis.

Results: 15d-PGJ2 showed cytotoxicity in dose-dependent manner. 15d-PGJ2 induced chromatin-condensation and elevated caspase-3 activity, and the cell viability was restored by co-treatment with a pan-caspase inhibitor, Z-VAD-FMK, indicating the involvement of caspase-dependent apoptosis. The cytotoxicity was not impaired by a PPARγ inhibitor, GW9662, suggesting that 15d-PGJ2 exerted the cytotoxicity in a PPARγ-independent manner. Some antioxidants rescued cells from cell death induced by 15d-PGJ2, but some did not, suggesting that reactive oxygen species (ROS) did not contribute to the apoptosis. 15d-PGJ2 also increased the expression levels of phospho-c-Jun N terminal kinase (JNK) in Caki-2 cells, and decreased those of phospho-Akt in 786-O cells, indicating that the JNK MAPK and the Akt pathways participated in the anticancer effects of 15d-PGJ2 in some cell lines.

Conclusion: 15d-PGJ2 exerted cytotoxic effects accompanying caspase-dependent apoptosis, and this effect was elicited in a PPARγ-independent manner in three cell lines. In addition, the JNK MAPK and Akt pathway was involved in the cytotoxicity of 15d-PGJ2 to some extent in some cell line. Therefore, our study showed the 15d-PGJ2 to potentially be an interesting approach for RCC treatment.

Keywords: 15-deoxy-Δ12,14prostaglandin J2, PPARγ, Renal cell carcinoma, Apoptosis, JNK MAPK, Akt.