CYTOTOXIC EFFECT OF 15d-PGJ2 AGAINST UTERINE SALCOMA
Kawakita, Takako Tokushima University Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Nisimura, Masato Tokushima University Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Takiguchi, Eri Tokushima University
Abe, Akiko Tokushima University Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Thesis or Dissertation
Effective chemotherapeutic strategies for uterine sarcoma are lacking; existing therapies achieve poor response rates. Previous studies have identified the prostaglandin 15-deoxy- Δ12,14-prostaglandin J2 (15d-PGJ2) as a potential anticancer treatment; however, its effectiveness in uterine sarcoma has not been examined. Furthermore, the molecular mechanisms underlying the cytotoxic mechanism of 15d-PGJ2 remain unclear. Here, we evaluated the effects of 15d-PGJ2 alone and in combination with the tyrosine kinas inhibitor (TKI) dasatinib in uterine sarcoma cell lines (MES-SA, MES-SA/DX5 and SKN). 15d-PGJ2 inhibited cell growth and increased apoptosis. Western blotting demonstrated that 15d-PGJ2 treatment increased MEK and ERK phosphorylation, and decreased levels of phosphorylated AKT. Dasatinib in combination with 15d-PGJ2 significantly reduced cell proliferation compared with 15d-PGJ2 alone, and repressed both the AKT and MAPK pathways. The cell growth inhibition rate in the PGJ2 was 21.5±12.0, 35.3±5.4 and 28.3±4.2%, respectively (MES-SA, MES-SA/DX5 and SKN cell lines) and the cell growth inhibition rate in the combination therapy was significantly higher compared with 15d-PGJ2 alone (MES-SA; 64.2±0.8, MES-SA/DX5;23.9±8.2 and SKN; 41.4±17.6%). The PGJ2 IC50 determined by MTT assay was 27.41,10.46 and 17.38 μmol/l, respectively (MES-SA, MES-SA/DX5 and SKN cell lines) and the dasatinib IC50 was 6.68,17.30 and 6.25 μmol/l, respectively. Our findings demonstrate that 15d-PGJ2 suppresses proliferation by inactivating the AKT pathway in uterine sarcoma. Furthermore, combining 15d-PGJ2 with dasatinib produced a synergistic effect on cancer cell inhibition by repressing 15d-PGJ2-mediated activation of MAPK signaling, and further repressing AKT signaling. These results suggest that 15d-PGJ2 could be used in combination with dasatinib as a potential therapeutic approach for uterine sarcoma.
Experimental and Therapeutic Medicine
© Kawakita et al. This is an open access article distributed under the terms of Creative Commons Attribution License (https://creativecommons.org/licenses/by-nc-nd/4.0/).
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LID201705191007.pdf 337 KB
LID201706261001.pdf 2.36 MB
|MEXT report number||
Doctor of Medical Science