title: Enterolactone inhibits insulin-like growth factor-1 receptor signaling in human prostatic carcinoma PC-3 cells.
abstract: Enterolactone, a major metabolite of plant-based lignans, has been shown to inhibit prostate cancer growth and development, but the mechanistic basis for its anticancer activity remains largely unknown. Activation of insulin-like growth factor-1 (IGF-1) receptor (IGF-1R) signaling is critical for prostate cancer cell growth and progression. This study examined whether the growth inhibitory effect of enterolactone was related to changes in the IGF-1/IGF-1R system in PC-3 prostate cancer cells. At nutritionally relevant concentrations (20-60 micromol/L), enterolactone inhibited IGF-1-induced activation of IGF-1R and its downstream AKT and mitogen-activated protein kinase/extracellular-signal regulated kinase signaling pathways. Inhibition of AKT by enterolactone resulted in decreased phosphorylation of its downstream targets, including p70S6K1 and glycogen synthase kinase-3 beta. Enterolactone also inhibited cyclin D1 expression. As a result, enterolactone inhibited proliferation and migration of PC-3 cells. Knockdown of IGF-1R by plasmids with siRNA (si) against IGF-1R mRNA resulted in inhibition of proliferation of PC-3 cells and cell numbers did not differ when the si-IGF-1R groups (cells transfected with plasmids containing siRNA against IGF-1R mRNA) were treated or untreated with enterolactone. These results suggest that enterolactone suppresses proliferation and migration of prostate cancer cells, at least partially, through inhibition of IGF-1/IGF-1R signaling. The finding of this study provides new insights into the molecular mechanisms that enterolactone exerts against prostate cancer.
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Li-Hua
authors.initials: LH
authors.lastname: Chen
authors.forename: Jing
authors.initials: J
authors.lastname: Fang
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Sun
authors.forename: Huaixing
authors.initials: H
authors.lastname: Li
authors.forename: Ying
authors.initials: Y
authors.lastname: Wu
authors.forename: Wendy
authors.initials: W
authors.lastname: Demark-Wahnefried
authors.forename: Xu
authors.initials: X
authors.lastname: Lin
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D017705:Lignans / Q000494:pharmacology*; D008297:Male; D019000:Phosphotyrosine / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D017705:Lignans; D019000:Phosphotyrosine; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D015107:4-Butyrolactone; C029497:2,3-bis(3'-hydroxybenzyl)butyrolactone