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

• Published in: Neoplasia (New York, N.Y.) Vol. 6; no. 4; pp. 354 - 363
• Main Authors: Li, Yiwei, Che, Mingxin, Bhagat, Sunita, Ellis, Kerrie-Lynn, Kucuk, Omer, Doerge, Daniel R., Abrams, Judith, Cher, Michael L., Sarkar, Fazlul H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2004; Elsevier
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - therapeutic use; bone metastasis; Bone Neoplasms - prevention & control; Bone Neoplasms - secondary; Cell Line, Tumor; Diet; gene expression; Gene Expression Regulation, Neoplastic - drug effects; Genistein; Genistein - administration & dosage; Genistein - therapeutic use; Humans; Male; Matrix Metalloproteinases - genetics; Mice; Mice, SCID; microarray; prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - pathology; Transplantation, Heterologous; PAR-2; RANKL; bone metastasis; Genistein; MMPs; OPG; uPA; RANK; SCID-hu; prostate cancer; microarray; SFRP; PDCD4; APG; uPAR; gene expression
• ISSN: 1476-5586; 1522-8002; 1476-5586; 1522-8002
• DOI: 10.1593/neo.03478

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.