title: (E)-2-methoxy-4-(3-(4-methoxyphenyl)prop-1-en-1-yl)phenol suppresses ovarian cancer cell growth via inhibition of ERK and STAT3.
abstract: In the present study, we synthesized several non-aldehyde analogues of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal which showed anti-cancer effect. Interestingly, among the 16 compounds, we found that (E)-2-methoxy-4-(3-(4-methoxyphenyl)prop-1-en-1-yl)phenol (MMPP) showed the most significant anti-proliferative effect on PA-1 and SK-OV-3 ovarian epithelial cancer cells. MMPP treatment (0-15 µg/mL) induced apoptotic cell death, enhanced the expression of cleaved caspase-3, and cleaved caspase-9 in a concentration dependent manner. Notably, DNA binding activity of STAT3, phosphorylation of extracellular signal-regulated kinase (ERK) and p38 was significantly decreased by MMPP treatment. However, ERK siRNA augmented MMPP-induced inhibitory effect on cell growth rather than p38 siRNA or JNK siRNA. Moreover, combination treatment of MMPP with ERK inhibitor U0126 (10 µM) augmented MMPP-induced inhibitory effect on cell growth and DNA binding activity of STAT3, and enhanced expression of cleaved caspase-3 and cleaved caspase-9. In addition, STAT3 siRNA transfection augmented MMPP-induced cell growth inhibition. In PA-1 bearing xenograft mice model, MMPP (5 mg/kg) suppressed tumor growth significantly. Immunohistochemistry staining showed that the expression levels of p-ERK, PCNA, p-STAT3 were decreased while the expression level of caspase-3 was increased by MMPP treatment. Thus, MMPP may be a promising anti-cancer agent in ovarian epithelial cancer treatment.
authors.affiliation: College of Pharmacy & Medical Research Center, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea.
authors.forename: Jie
authors.initials: J
authors.lastname: Zheng
authors.affiliation: College of Pharmacy & Medical Research Center, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea.
authors.forename: Dong Ju
authors.initials: DJ
authors.lastname: Son
authors.affiliation: College of Pharmacy & Medical Research Center, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea.
authors.forename: Hye Lim
authors.initials: HL
authors.lastname: Lee
authors.affiliation: College of Pharmacy & Medical Research Center, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea.
authors.forename: Hee Pom
authors.initials: HP
authors.lastname: Lee
authors.affiliation: College of Pharmacy & Medical Research Center, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea.
authors.forename: Tae Hoon
authors.initials: TH
authors.lastname: Kim
authors.affiliation: College of Pharmacy & Medical Research Center, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea.
authors.forename: Jung Heun
authors.initials: JH
authors.lastname: Joo
authors.affiliation: Department of Chemistry, Utah Valley University 800 W, University Pkwy, Orem, Utah.
authors.forename: Young Wan
authors.initials: YW
authors.lastname: Ham
authors.affiliation: College of Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea.
authors.forename: Wun Jae
authors.initials: WJ
authors.lastname: Kim
authors.affiliation: College of Pharmacy & Medical Research Center, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea.
authors.forename: Jae Kyung
authors.initials: JK
authors.lastname: Jung
authors.affiliation: College of Pharmacy & Medical Research Center, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea.
authors.forename: Sang-Bae
authors.initials: SB
authors.lastname: Han
authors.affiliation: College of Pharmacy & Medical Research Center, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea.
authors.forename: Jin Tae
authors.identifier: 0000-0002-6534-9575
authors.initials: JT
authors.lastname: Hong
mesh_terms: D000447:Aldehydes / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004273:DNA, Neoplasm / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D005260:Female; D006139:Guaiacol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy*; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D010636:Phenols / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*
chemical_list: C580808:2,4-bis(p-hydroxyphenyl)-2-butenal; C000623019:2-methoxy-4-(3-(4-methoxyphenyl)prop-1-en-1-yl)phenol; D000447:Aldehydes; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D004273:DNA, Neoplasm; D010636:Phenols; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D006139:Guaiacol; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: ERK; MMPP; STAT3; apoptosis; ovarian epithelial cancer