Prostaglandin F_(2α)synthase promotes oxaliplatin resistance in colorectal cancer through prostaglandin F_(2α)-dependent and F_(2α)-independent mechanism  

作　　者：Yi-Jun Wang Xiao-Li Xie Hong-Qun Liu Hui Tian Xiao-Yu Jiang Jiu-Na Zhang Sheng-Xiong Chen Ting Liu Shu-Ling Wang Xue Zhou Xiao-Xu Jin Shi-Mao Liu Hui-Qing Jiang 

机构地区：[1]Department of Gastroenterology,The Second Hospital of Hebei Medical University,Shijiazhuang 050000,Hebei Province,China [2]Liver Unit,University of Calgary,Calgary T1W0K6,Canada [3]Department of Gastroenterology,The Affiliated Hospital of Hebei Engineering University,Handan 056000,Hebei Province,China [4]Department of Hepatobiliary Surgery,The Second Hospital of Hebei Medical University,Shijiazhuang 050000,Hebei Province,China [5]Department of Gastroenterology,The First Hospital of Hebei Medical University,Shijiazhuang 050000,Hebei Province,China [6]Department of Gastroenterology,Hebei Youfu Hospital,Shijiazhuang 050000,Hebei Province,China

出　　处：《World Journal of Gastroenterology》2023年第39期5452-5470,共19页世界胃肠病学杂志（英文版）

基　　金：the S and T Program of Hebei,No.22377704D;Medical Science Research Project of Hebei Province,No.20190510;Postgraduate’s Innovation Fund Project of Hebei Province,No.CXZZBS2021077.

摘　　要：BACKGROUND Oxaliplatin(Oxa)is the first-line chemotherapy drug for colorectal cancer(CRC),and Oxa resistance is crucial for treatment failure.Prostaglandin F_(2α)synthase(PGF 2α)(PGFS),an enzyme that catalyzes the production of PGF_(2α),is involved in the proliferation and growth of a variety of tumors.However,the role of PGFS in Oxa resistance in CRC remains unclear.AIM To explore the role and related mechanisms of PGFS in mediating Oxa resistance in CRC.METHODS The PGFS expression level was examined in 37 pairs of CRC tissues and paracancerous tissues at both the mRNA and protein levels.Overexpression or knockdown of PGFS was performed in CRC cell lines with acquired Oxa resistance(HCT116-OxR and HCT8-OxR)and their parental cell lines(HCT116 and HCT8)to assess its influence on cell proliferation,chemoresistance,apoptosis,and DNA damage.For determination of the underlying mechanisms,CRC cells were examined for platinum-DNA adducts and reactive oxygen species(ROS)levels in the presence of a PGFS inhibitor or its products.RESULTS Both the protein and mRNA levels of PGFS were increased in the 37 examined CRC tissues compared to the adjacent normal tissues.Oxa induced PGFS expression in the parental HCT116 and HCT8 cells in a dosedependent manner.Furthermore,overexpression of PGFS in parental CRC cells significantly attenuated Oxainduced proliferative suppression,apoptosis,and DNA damage.In contrast,knockdown of PGFS in Oxa-resistant HCT116 and HCT8 cells(HCT116-OxR and HCT8-OxR)accentuated the effect of Oxa treatment in vitro and in vivo.The addition of the PGFS inhibitor indomethacin enhanced the cytotoxicity caused by Oxa.Treatment with the PGFS-catalyzed product PGF_(2α)reversed the effect of PGFS knockdown on Oxa sensitivity.Interestingly,PGFS inhibited the formation of platinum-DNA adducts in a PGF_(2α)-independent manner.PGF_(2α)exerts its protective effect against DNA damage by reducing ROS levels.CONCLUSION PGFS promotes resistance to Oxa in CRC via both PGF_(2α)-dependent and PGF_(2α)-independent m

关 键 词：Prostaglandin F_(2α)synthase Colorectal cancer OXALIPLATIN Drug resistance DNA damage 

分 类 号：R735.34[医药卫生—肿瘤]