Mechanisms controlling cell cycle arrest and induction of apoptosis after 12-lipoxygenase inhibition in prostate cancer cells.
Mechanisms controlling cell cycle arrest and induction of apoptosis after 12-lipoxygenase inhibition in prostate cancer cells.
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发表时间：
2002-05
期刊：
影响因子：
11.2
通讯作者：
G. Pidgeon;M. Kandouz;Anthony Meram;K. Honn
中科院分区：
文献类型：
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作者：
G. Pidgeon;M. Kandouz;Anthony Meram;K. Honn
大量研究表明膳食脂肪酸在前列腺癌进展中的作用。血小板型12-脂氧合酶（12-LOX）已被证明可调节前列腺癌的生长、转移和血管生成。研究了黄芩素和n -苄基- n -羟基-5-苯基五胺（BHPP）两种12-LOX抑制剂对前列腺癌细胞PC3和DU-145细胞周期进程和凋亡的调控作用。通过BrdUrd掺入测量，黄芩素或BHPP治疗导致细胞增殖的剂量依赖性降低。这种生长停滞是由于细胞周期在G0/G1时受到抑制，并与细胞周期蛋白D1和D3水平的抑制有关。PC3细胞磷酸化的视网膜母细胞瘤（pRB）蛋白也明显减少，而其他视网膜母细胞瘤相关蛋白p107和p130在DU-145细胞中被抑制。在黄芩素存在的情况下，用12-羟基二碳四烯酸处理可阻断pRB的丢失，而单独使用12(S)-HETE可诱导pRB的表达。通过末端脱氧核苷酸转移酶介导的dUTP缺口末端标记，黄芩素或BHPP处理均导致两种细胞系显著凋亡。DU-145细胞比PC-3细胞凋亡更快。其机制包括Akt磷酸化降低、survivin缺失以及随后在各细胞系中caspase-3和caspase-7的激活，DU-145中Bcl-2和Bcl-X(L)表达降低，PC-3细胞中Bcl-2/Bax水平的变化有利于细胞凋亡。添加12(S)-HETE可以保护两种细胞系免受黄芩素诱导的凋亡，而其他LOX代谢物，5(S)-HETE或15(S)-HETE则没有作用。这些结果表明，12-LOX通路是前列腺癌进展和细胞凋亡的关键调节因子，通过影响调节这些过程的各种蛋白。因此，抑制12-LOX是一种潜在的治疗前列腺癌的药物。
Extensive studies have implicated the role of dietary fatty acids in prostatecancer progression. Platelet-type 12-Lipoxygenase (12-LOX) has beenshown to regulate growth, metastasis, and angiogenesis of prostate cancer. The effect of two 12-LOX inhibitors, Baicalein and N-benzyl-N-hydroxy-5-phenylpentamide (BHPP), on the mechanisms controlling cell cycle progression and apoptosis were examined in two prostate cancer cell lines, PC3 and DU-145. Treatment with Baicalein or BHPP resulted in a dose-dependent decrease in cell proliferation, as measured by BrdUrd incorporation. This growth arrest was shown to be because of cell cycle inhibition at G0/G1, and was associated with suppression of cyclin D1 and D3 protein levels. PC3 cells also showed a strong decrease in phosphorylated retinoblastoma (pRB) protein, whereas the other retinoblastoma-associated proteins, p107 and p130, were inhibited in DU-145 cells. Treatment with 12-hydroxyeicosatetraenoic acid in the presence of Baicalein blocked loss of pRB, whereas 12(S)-HETE alone induced pRB expression. Treatment with either Baicalein or BHPP resulted in significant apoptosis in both cell lines as measured by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling. DU-145 cells underwent apoptosis more rapidly than PC-3 cells. The mechanisms involved were decreased phosphorylation of Akt, loss of survivin and subsequent activation of caspase-3 and caspase-7 in each cell line, decreased Bcl-2 and Bcl-X(L) expression in DU-145, and a shift in Bcl-2/Bax levels favoring apoptosis in PC-3 cells. Addition of 12(S)-HETE protected both cell lines from Baicalein-induced apoptosis, whereas other LOX metabolites, 5(S)-HETE, or 15(S)-HETE did not. These results show that the 12-LOX pathway is a critical regulator of prostate cancer progression and apoptosis, by affecting various proteins regulating these processes. Therefore, inhibition of 12-LOX is a potential therapeutic agent in the treatment of prostate cancer.