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: Li-Hua Chen, Jing Fang, Zhijian Sun, Huaixing Li, Ying Wu, Wendy Demark-Wahnefried, Xu Lin
• Journal: The Journal of nutrition (J Nutr) Vol. 139 Issue 4 Pg. 653-9 (Apr 2009) ISSN: 1541-6100 [Electronic] United States
• PMID: 19211828 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Lignans
• Phosphotyrosine
• Insulin-Like Growth Factor I
• Receptor, IGF Type 1
• Proto-Oncogene Proteins c-akt
• 4-Butyrolactone
• 2,3-bis(3'-hydroxybenzyl)butyrolactone

Topics

• 4-Butyrolactone (analogs & derivatives, pharmacology)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Insulin-Like Growth Factor I (pharmacology)
• Lignans (pharmacology)
• Male
• Phosphotyrosine (metabolism)
• Prostatic Neoplasms (metabolism, pathology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Receptor, IGF Type 1 (antagonists & inhibitors, genetics, metabolism)
• Signal Transduction (drug effects)