ID 112972
Title Alternative
15-deoxy-Δ12,14-prostaglandin J2の単剤とダサチニブの併用療法は子宮肉腫の増殖を抑制する
CYTOTOXIC EFFECT OF 15d-PGJ2 AGAINST UTERINE SALCOMA
Author
Takiguchi, Eri Tokushima University
Keywords
15‑deoxy‑Δ12,14‑prostaglandin J2
uterine sarcoma
dasatinib
MAPK
ERK
AKT
Content Type
Thesis or Dissertation
Description
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.
Journal Title
Experimental and Therapeutic Medicine
ISSN
17920981
17921015
NCID
AA12610820
Publisher
Spandidos publications
Volume
13
Issue
6
Start Page
2939
End Page
2945
Published Date
2017-04-18
Remark
内容要旨・審査要旨・論文本文の公開:
内容要旨・審査要旨:LID201705191007.pdf
論文本文:LID201706261001.pdf
本論文は,著者TAKAKO KAWAKITAの学位論文として提出され,学位審査・授与の対象となっている。
著者の申請により要約(2017-05-19公開)に替えて論文全文を公開(2017-06-26)
Rights
© 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/).
EDB ID
DOI (Published Version)
URL ( Publisher's Version )
FullText File
language
eng
TextVersion
ETD
MEXT report number
甲第3021号
Diploma Number
甲医第1325号
Granted Date
2017-03-06
Degree Name
Doctor of Medical Science
Grantor
Tokushima University
departments
University Hospital
Medical Sciences