Vitamin D receptor and p21/WAF1 are targets of genistein and 1,25-dihydroxyvitamin D3 in human prostate cancer cells.
We investigated mechanisms by which genistein and 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] act synergistically to inhibit the growth of the human prostate cancer cell line LNCaP. We demonstrate that 1,25(OH)(2)D(3) and genistein cooperate to up-regulate the vitamin D receptor protein by increasing the stability of the vitamin D receptor. Genistein and 1,25(OH)(2)D(3) also cooperate to up-regulate the levels of p21/WAF1 (p21). Small interfering RNA-mediated knockdown of p21 expression showed that p21 is essential for significant growth inhibition of LNCaP cells in response to either compound or their combination. We conclude that one mechanism of synergism between genistein and 1,25(OH)(2)D(3) is through genistein modulation of vitamin D signaling.
Rao
Anuradha
A
Department of Cancer Biology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
Coan
April
A
Welsh
Jo-Ellen
JE
Barclay
Wendy W
WW
Koumenis
Constantinos
C
Cramer
Scott D
SD
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002117:Calcitriol / Q000627:therapeutic use*; D002120:Calcium Channel Agonists / Q000627:therapeutic use; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000378:metabolism; D019833:Genistein / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000494:pharmacology; D018167:Receptors, Calcitriol / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D002120:Calcium Channel Agonists; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; D018167:Receptors, Calcitriol; D019833:Genistein; D002117:Calcitriol