Enterolactone inhibits insulin-like growth factor-1 receptor signaling in human prostatic carcinoma PC-3 cells.
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.
Chen
Li-Hua
LH
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.
Fang
Jing
J
Sun
Zhijian
Z
Li
Huaixing
H
Wu
Ying
Y
Demark-Wahnefried
Wendy
W
Lin
Xu
X
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*
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