Elsevier

Neoplasia

Volume 6, Issue 4, July–August 2004, Pages 354-363
Neoplasia

Regulation of Gene Expression and Inhibition of Experimental Prostate Cancer Bone Metastasis by Dietary Genistein1

https://doi.org/10.1593/neo.03478 Get rights and content
Under a Creative Commons license
open access

Abstract

Prostate cancer frequently metastasizes to the bone, and the treatment outcome for metastatic prostate cancer has been disappointing so far. Dietary genistein, derived primarily from soy product, has been proposed to be partly responsible for the low rate of prostate cancer in Asians. Our previous studies have shown that genistein elicits pleiotropic effects on prostate cancer cells, but there are no studies documenting comprehensive gene expression profiles and antitumor effects of dietary genistein on human prostate cancer grown in human bone environment. In this study, we investigated the effects of genistein on PC3 prostate cancer cells and experimental PC3 bone tumors created by injecting PC3 cells into human bone fragments previously implanted in severe combined immunodeficient (SCID) mice (SCID human model). We found that genistein significantly inhibited PC3 bone tumor growth using both prevention and intervention strategies. By using microarray and real-time polymerase chain reaction technology, we found that genistein regulated the expression of multiple genes involved in the control of cell growth, apoptosis, and metastasis both in vitro and in vivo. For example, the expression of various metalloproteinases (MMPs) in PC3 bone tumors was inhibited by genistein treatment, whereas osteoprotegerin was upregulated. MMP immunostaining and transfection experiments also demonstrated that MMP-9 expression was inhibited in PC3 cells in vitro and PC3 bone tumors in vivo after genistein treatment. These results, particularly the in vivo results, demonstrate that dietary genistein may inhibit prostate cancer bone metastasis by regulating metastasis-related genes. Genistein may thus be a promising agent for the prevention and/or treatment of prostate cancer.

Keywords

Genistein
prostate cancer
bone metastasis
microarray
gene expression

Abbreviations

SCID-hu
severe combined immunodeficient-human
MMPs
metalloproteinases
RANK
receptor activator of NF-κB
RANKL
receptor activator of NF-κB ligand
OPG
osteoprotegerin
PDCD4
programmed cell death 4
APG
apoptosis-related protein
SFRP
secreted frizzled-related protein
uPA
urokinase plasminogen activator
uPAR
urokinase plasminogen activator receptor
PAR-2
protease-activated receptor-2

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1

This work was partly funded by grants from the National Cancer Institute, National Institute of Health (CA83695-01 A2 to F.H.S. and CA-88028 to M.L.C.).