title: Generation of ROS by CAY10598 leads to inactivation of STAT3 signaling and induction of apoptosis in human colon cancer HCT116 cells.
abstract: Prostaglandin E2 (PGE2) has been reported to play critical roles in cell fate decision by interacting with four types of prostanoid receptors such as EP1, EP2, EP3 and EP4. The present study was aimed at investigating the effect of the EP4-specific agonist CAY10598 in human colon cancer HCT116 cells. Our study revealed that treatment with CAY10598 significantly reduced the cell viability and induced apoptosis in HCT116 cells, as evidenced by the induction of p53 and Bax, release of cytochrome c, cleavage of caspase-9, -7, and -3, and PARP, and the inhibition of Bcl-2, Bcl-xL and survivin expression. Moreover, treatment with CAY10598 diminished the phosphorylation of JAK2, leading to the attenuation of STAT3 activation in HCT116 cells. CAY10598-induced apoptosis in cells which were transiently transfected with EP4 siRNA or treated with an EP4 antagonist prior to incubation with the compound remained unaffected, suggesting an EP4-independent mechanism of apoptosis induction by CAY10598. We found that treatment with CAY10598 generated reactive oxygen species (ROS) and pretreatment of cells with N-acetyl cysteine rescued cells from apoptosis by abrogating the inhibitory effect of CAY10598 on the activation of JAK2/STAT3 signaling. In conclusion, CAY10598 induced apoptosis in HCT116 cells in an EP4-independent manner, but through the generation of ROS and inactivation of JAK2/STAT3 signaling.
authors.affiliation: College of Pharmacy, Keimyung University , Daegu , South Korea.
authors.forename: I G
authors.initials: IG
authors.lastname: Chae
authors.forename: D-H
authors.initials: DH
authors.lastname: Kim
authors.forename: J
authors.initials: J
authors.lastname: Kundu
authors.forename: C-H
authors.initials: CH
authors.lastname: Jeong
authors.forename: J K
authors.initials: JK
authors.lastname: Kundu
authors.forename: K-S
authors.initials: KS
authors.lastname: Chun
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D015232:Dinoprostone / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D011760:Pyrrolidinones / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000819:agonists*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: C000598602:CAY10598; D011760:Pyrrolidinones; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D058309:Receptors, Prostaglandin E, EP4 Subtype; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013777:Tetrazoles; D015232:Dinoprostone
keywords: CAY10598; EP4 receptor; ROS; STAT3; colon cancer cells