title: Antiproliferative effects of Dangyuja (Citrus grandis Osbeck) leaves through suppression of constitutive signal transducer and activator of transcription 3 activation in human prostate carcinoma DU145 cells.
abstract: Although Dangyuja (Citrus grandis Osbeck) exhibits anti-inflammatory and anticancer activities, its molecular targets and pathways, especially in human prostate cancer cells, are not fully understood. In this study, the antiproliferative effect of Dangyuja leaves through the signal transducer and activator of transcription (STAT) 3 signaling pathway was investigated in human prostate carcinoma DU145 cells. The solvent fractions (n-hexane, chloroform, ethyl acetate, and n-butanol) were obtained from a crude extract (80% methanol extract) of Dangyuja leaves. We first found that the chloroform fraction of Dangyuja leaves (DCF) was the most cytotoxic against DU145 cells. DCF inhibited constitutive STAT3 activation through blocking upstream Janus-like kinase 2 and c-Src. Consistent with STAT3 inactivation, DCF down-regulated the expression of STAT3 target genes, including bcl-2, bcl-xl, and cyclin D1; this correlated with the suppression of proliferation, the accumulation of cell cycle at the sub-G(1) phase, and the induction of apoptosis. Furthermore, DCF exerted a relatively minor effect on the growth of human prostate noncancerous RWPE-1 cells. Nobiletin, a major active constituent of DCF, could induce apoptosis via the suppression of constitutive STAT3 activation. Overall, our results indicate that the anti-inflammatory and anticancer activities previously assigned to DCF may be mediated partially through the suppression of the STAT3 signaling.
authors.affiliation: College of Oriental Medicine, Kyung Hee University, Seoul, Korea.
authors.forename: Shu Yuan
authors.initials: SY
authors.lastname: Chiang
authors.forename: Sung-Moo
authors.initials: SM
authors.lastname: Kim
authors.forename: Chulwon
authors.initials: C
authors.lastname: Kim
authors.forename: Jae-Young
authors.initials: JY
authors.lastname: Um
authors.forename: Kyung-Ran
authors.initials: KR
authors.lastname: Park
authors.forename: Seong Won
authors.initials: SW
authors.lastname: Kim
authors.forename: Seok-Geun
authors.initials: SG
authors.lastname: Lee
authors.forename: Hyeung-Jin
authors.initials: HJ
authors.lastname: Jang
authors.forename: Dongwoo
authors.initials: D
authors.lastname: Nam
authors.forename: Kyoo Seok
authors.initials: KS
authors.lastname: Ahn
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Kim
authors.forename: Seung-Hoon
authors.initials: SH
authors.lastname: Choi
authors.forename: Bum Sang
authors.initials: BS
authors.lastname: Shim
authors.forename: Yun-Cheol
authors.initials: YC
authors.lastname: Na
authors.forename: Eun-Kyung
authors.initials: EK
authors.lastname: Jeong
authors.forename: Somi K
authors.initials: SK
authors.lastname: Cho
authors.forename: Kwang Seok
authors.initials: KS
authors.lastname: Ahn
mesh_terms: D002277:Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002957:Citrus / Q000737:chemistry*; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D008297:Male; D010936:Plant Extracts / Q000494:pharmacology*; D018515:Plant Leaves / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D006131:Growth Inhibitors; D010936:Plant Extracts; D050796:STAT3 Transcription Factor