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Carcinogenesis Advance Access originally published online on October 25, 2006
Carcinogenesis 2007 28(3):713-723; doi:10.1093/carcin/bgl189
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Luteolin inhibits insulin-like growth factor 1 receptor signaling in prostate cancer cells

Jing Fang1,*,{dagger}, Qiong Zhou1,{dagger}, Xiang-lin Shi1 and Bing-hua Jiang1,2

1 The Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Graduate School of Chinese Academy of Sciences Shanghai 200031, China
2 The Department of Microbiology, Cell Biology and Immunology, MBR Cancer Center, West Virginia University Morgantown, WV 26506, USA

*To whom correspondence should be addressed. Tel: +86 21 54920241; Fax: +86 21 54920291; Email: jfang{at}sibs.ac.cn

Insulin-like growth factor 1 receptor (IGF-1R) activation is required for prostate cell proliferation. Prostate cancer is one of the most commonly diagnosed malignant tumors in Western countries. Overexpression of IGF-1R in prostate cancer is associated with tumor growth. These suggest that IGF-1R inhibitory agents may be of preventive and/or therapeutic value. With evidence accumulating for a chemopreventive role of flavonoids, the effects of luteolin, a bioactive flavonoid, on IGF-1R signaling in prostate cancer cells were examined. Luteolin inhibited insulin-like growth factor 1 (IGF-1) induced activation of IGF-1R and AKT in prostate cancer PC-3 and DU145 cells. Inhibition of AKT by luteolin resulted in decreased phosphorylation of its downstream targets, including p70S6K1, GSK-3ß and FKHR/FKHRL1. Luteolin also inhibited the IGF-1-induced activation of EGFR and MAPK/ERK signaling. Luteolin inhibited expression of cyclin D1 and increased expression of p21. As a result, luteolin suppressed proliferation and induced apoptosis of prostate cancer cells. Knockdown of IGF-1R by siRNA led to inhibition of proliferation of prostate cancer cells. Results of in vivo tumor growth assay indicated that luteolin inhibited PC-3 tumor growth. Immunoblotting of the extracts of tumor tissues showed that luteolin inhibited IGF-1R/AKT signaling. Our results provide a new insight into the mechanisms that luteolin is against cancer cells.

Abbreviations: IGF, insulin-like growth factor; IGF-1, insulin-like growth factor 1; IGF-1R, insulin-like growth factor 1 receptor; IGFBP, insulin-like growth factor binding protein; EGFR, epidermal growth factor receptor; ERK, extracellular-signal regulated kinase; GSK-3ß, Glycogen Synthase Kinase 3beta

{dagger}These authors contributed equally to this work.

Received March 29, 2006; revised September 27, 2006; accepted September 29, 2006.


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