Multiple Sites of Type II Site Ligand (Luteolin and BMHPC) Regulation of Gene Expression in PC-3 Cells
Multiple Sites of Type II Site Ligand (Luteolin and BMHPC) Regulation of Gene Expression in PC-3 Cells
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DOI：
10.59566/ijbs.2012.8219
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发表时间：
2012-12
期刊：
影响因子：
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通讯作者：
B. Markaverich;Mary Vijjeswarapu
中科院分区：
文献类型：
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作者：
B. Markaverich;Mary Vijjeswarapu
II型[3 H]雌二醇结合位点配体，包括毛地黄黄酮（天然存在的双黄酮）和合成化合物如2，6-双（（3-甲氧基-4-羟基苯基）亚甲基）环己酮（BMHPC），在体外和体内抑制正常和恶性前列腺细胞（PC-3、LNCaP、DU-145）增殖。II型位点代表组蛋白H4上的结合域，可能参与控制基因转录的表观遗传机制。用毛地黄黄酮或BMHPC处理PC-3人前列腺癌细胞可调节表皮生长因子受体信号通路（EGFRSP）和细胞周期通路（CCP）中许多基因的表达。观察到c-FOS和p21 RNA表达的明显刺激（对照的400-2000%），表明这些是主要的作用位点。两种化合物也引起不可逆的G2/M停滞（p<0.001）。针对c-FOS或p21的siRNA使其各自靶的RNA表达降低85- 95%，对细胞增殖的影响最小。此外，siRNA单独（单敲低）或组合（双敲低）均不能阻断毛地黄黄酮或BMHPC对PC-3细胞增殖的抑制。因此，尽管已知c-FOS和p21调节ESGRSP中基因的表达，（EGFR、SOS、GRB 2、JNK 1、MKK 4、RasGAP）和CCP（CCNA 2、CCNE 2、CDC 25 A、CDKN 1A、CDKN 1B、p27、PLK 1）参与毛地黄黄酮和BMHPC对细胞增殖的调节，本文报道的c-FOS和p21 siRNA敲低研究表明，在PC-3细胞增殖调节中，c-FOS和p21可能是对这些配体的总体应答中的次要旁观者。
Type II [3H]estradiol binding site ligands including luteolin (a naturally occurring bioflavonoid) and synthetic compounds such as 2,6-bis((3-methoxy-4-hydroxyphenyl)methylene)cyclohexanone (BMHPC) inhibit normal and malignant prostate cell (PC-3, LNCaP, DU-145) proliferation in vitro and in vivo. Type II sites represent a binding domain on histone H4 possibly involved in an epigenetic mechanism for controlling gene transcription. Treatment of PC-3 human prostate cancer cells with luteolin or BMHPC modulated the expression of a number of genes in the epidermal growth factor receptor signaling pathway (EGFRSP) and cell cycle pathway (CCP). Pronounced stimulation (400-2000% of control) of c-FOS and p21 RNA expression was observed, suggesting that these were primary sites of action. Both compounds also caused irreversible G2/M arrest (p<0.001). siRNA’s for c-FOS or p21 reduced the RNA expression of their respective targets by 85-95%, with minimal effects on cell proliferation. Furthermore, neither siRNA alone (single knockdown), or in combination (double knockdown), blocked luteolin or BMHPC inhibition of PC-3 cell proliferation. Thus, although c-FOS and p21 are known to modulate the expression of genes in the ESGRSP (EGFR, SOS, GRB2, JNK1, MKK4, RasGAP) and CCP (CCNA2, CCNE2, CDC25A, CDKN1A, CDKN1B, p27, PLK1) involved in the regulation of cell proliferation by luteolin and BMHPC, the c-FOS and p21 siRNA knockdown studies reported here suggest that c-FOS and p21 may be secondary bystanders in the overall response to these ligands in the regulation of PC-3 cell proliferation.