Ikezoe Takayuki, Gery Sigal, Yin Dong, O'Kelly James, Binderup Lise, Lemp Nathan, Taguchi Hirokuni, Koeffler H Phillip
Division of Hematology/Oncology, Cedars-Sinai Medical Center, University of California at Los Angeles School of Medicine, Los Angeles, California, USA.
Cancer Res. 2005 Jun 1;65(11):4762-8. doi: 10.1158/0008-5472.CAN-03-3619.
1,25-Dihydroxyvitamin D3 [1,25(OH)2D3], the active metabolite of vitamin D3, inhibits the proliferation of prostate cancer cells. However, the molecular mechanisms by which 1,25(OH)2D3 inhibits the proliferation of these cells remain to be fully elucidated. In this study, we used microarray technology to identify target genes of 1,25(OH)2D3 in androgen-responsive prostate cancer LNCaP cells. 1,25(OH)2D3 up-regulated CCAAT/enhancer-binding protein delta (C/EBPdelta) by approximately 5-fold in these cells. Knockdown of C/EBPdelta expression by RNA interference showed that C/EBPdelta is essential for the significant growth inhibition of LNCaP cells in response to 1,25(OH)2D3 treatment. Moreover, we found that 1,25(OH)2D3 induced C/EBPdelta in other cancer cells, including the estrogen receptor (ER)-expressing MCF-7 and T47D breast cancer cells that are sensitive to the growth inhibitory effects of 1,25(OH)2D3. On the other hand, 1,25(OH)2D3 was not able to induce C/EBPdelta in either androgen receptor-negative PC-3 and DU145 or ER-negative breast cancer MDA-MB-231 cells that were relatively resistant to growth inhibition by 1,25(OH)2D3. Furthermore, forced expression of C/EBPdelta in prostate cancer LNCaP as well as breast cancer MCF-7 and T47D cells dramatically reduced their clonal growth. Taken together, forced expression of C/EBPdelta in cancer cells may be a promising therapeutic strategy.
1,25 - 二羟基维生素D3[1,25(OH)2D3]是维生素D3的活性代谢产物，可抑制前列腺癌细胞的增殖。然而，1,25(OH)2D3抑制这些细胞增殖的分子机制仍有待充分阐明。在本研究中，我们使用微阵列技术来鉴定雄激素反应性前列腺癌LNCaP细胞中1,25(OH)2D3的靶基因。在这些细胞中，1,25(OH)2D3使CCAAT/增强子结合蛋白δ（C/EBPδ）上调了约5倍。通过RNA干扰敲低C/EBPδ表达表明，C/EBPδ对于1,25(OH)2D3处理后LNCaP细胞的显著生长抑制至关重要。此外，我们发现1,25(OH)2D3在其他癌细胞中诱导C/EBPδ，包括对1,25(OH)2D3的生长抑制作用敏感的表达雌激素受体（ER）的MCF - 7和T47D乳腺癌细胞。另一方面，1,25(OH)2D3在雄激素受体阴性的PC - 3和DU145或对1,25(OH)2D3的生长抑制相对耐药的ER阴性乳腺癌MDA - MB - 231细胞中均无法诱导C/EBPδ。此外，在前列腺癌LNCaP以及乳腺癌MCF - 7和T47D细胞中强制表达C/EBPδ可显著降低它们的克隆生长。综上所述，在癌细胞中强制表达C/EBPδ可能是一种有前景的治疗策略。
