Soy isoflavones exert differential effects on androgen responsive genes in LNCaP human prostate cancer cells.
The high consumption of soy isoflavones in Asian diets has been correlated to a lower incidence of clinically important cases of prostate cancer. This study characterized the effects of a soy-derived isoflavone concentrate (ISF) on growth and gene expression profiles in the LNCaP, an androgen-sensitive human prostate cancer cell line. ISF caused a dose-dependent decrease in viability (P < 0.05) and DNA synthesis (P < 0.01), as well as an accumulation of cells in G(2)/M, and G(0)/G(1) phases of the cell cycle compared with controls. Using Affymetrix oligonucleotide DNA microarrays (U133A), we determined that ISF upregulated 80 genes and downregulated 33 genes (P < 0.05) involving androgen-regulated genes and pathways controlling cell cycle, metabolism, and intracellular trafficking. Changes in the expression of the genes of interest, identified by microarrays, were validated by Western immunoblot, Northern blot, and luciferase reporter assays. Prostate-specific antigen, homeobox protein NKX3, and cyclin B mRNA were significantly reduced, whereas mRNA was significantly upregulated for p21(CIP1), a major cell cycle inhibitory protein, and fatty acid and cholesterol synthesis pathway genes. ISF also significantly increased cyclin-dependent kinase inhibitor p27(KIP1) and FOXO3A/FKHRL1, a forkhead transcription factor. A differential pattern of androgen-regulated genes was apparent with genes involved in prostate cancer progression being downregulated by ISF, whereas metabolism genes were upregulated. In summary, we found that ISF inhibits the growth of LNCaP cells through the modulation of cell cycle progression and the differential expression of androgen-regulated genes. Thus, ISF treatment serves to identify new therapeutic targets designed to prevent proliferation of malignant prostate cells.
Rice
Lori
L
Department of Radiation Oncology, College of Medicine, University of Florida, Gainesville, FL 32610, USA. lrice@ufl.edu
Handayani
Renita
R
Cui
Yuehua
Y
Medrano
Theresa
T
Samedi
Von
V
Baker
Henry
H
Szabo
Nancy J
NJ
Rosser
Charles J
CJ
Goodison
Steve
S
Shiverick
Kathleen T
KT
D000728:Androgens / Q000378:metabolism*; D001682:Biological Availability; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003470:Culture Media / Q000378:metabolism; D019926:Cyclin B / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007529:Isoflavones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D017430:Prostate-Specific Antigen / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D013025:Glycine max / Q000737:chemistry*; D014158:Transcription, Genetic; D015854:Up-Regulation
D000728:Androgens; D003470:Culture Media; D019926:Cyclin B; D050759:Cyclin-Dependent Kinase Inhibitor p21; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D007529:Isoflavones; D012333:RNA, Messenger; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017430:Prostate-Specific Antigen