Androgen blocks apoptosis of hormone-dependent prostate cancer cells.
Androgen blocks apoptosis of hormone-dependent prostate cancer cells.
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发表时间：
2001-07
期刊：
影响因子：
11.2
通讯作者：
K. Kimura;Mark Markowski;C. Bowen;E. P. Gelmann
中科院分区：
文献类型：
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作者：
K. Kimura;Mark Markowski;C. Bowen;E. P. Gelmann
雄激素在前列腺癌的促进和生长中起着至关重要的作用。雄激素消融在前列腺癌治疗中发挥着越来越重要的作用，除了在转移性疾病的治疗中发挥作用外，现在还用于提高放射治疗的疗效。在这里，我们表明雄激素干扰由多种刺激诱导的前列腺癌细胞死亡。雄激素对细胞死亡的影响主要通过干扰 caspase 激活和抑制外源性和内源性细胞死亡途径中的 caspase 裂解来实现。雄激素可抑制由肿瘤坏死因子 α (TNF-α) 和 Fas 激活（无论有或没有伴随照射）诱导的细胞凋亡。在 R1881、二氢睾酮和 17β-雌二醇存在下，在死亡诱导 24 小时内观察到抗凋亡作用。仅使用 R1881、二氢睾酮、醋酸环丙孕酮和羟基氟他胺在 72 小时时观察到细胞凋亡的持续抑制。雄激素治疗通过 TNF-α +/- 照射抑制 caspase-8、-7 和 -9 的激活。雄激素减弱 BAX 表达并阻止 BAX 促凋亡 p18 片段的出现。雄激素还消除了 TNF-α + 照射诱导的 BID 裂解，从而导致 TNF-α +/- 照射诱导的细胞色素 c 从线粒体流出减少。 TNF-α + 照射引起的线粒体去极化也减少。促凋亡脂质代谢物神经酰胺的产生不受雄激素的影响，但雄激素在神经酰胺生成的下游起作用，因为 R1881 阻断了细菌鞘磷脂酶诱导细胞死亡。渥曼青霉素抑制磷酸肌醇-3-激酶活性可诱导细胞凋亡，这种细胞凋亡也被雄激素阻断，但对蛋白水平或 AKT 磷酸化没有影响，表明 R1881 不与磷酸肌醇-3-激酶的生存信号相互作用。最后，雄激素在死亡诱导过程中抑制核因子-kappaB 的激活，但雄激素对细胞死亡的影响并不是通过干扰核因子-kappaB 途径介导的。数据表明，雄激素诱导阻断内源性和外源性细胞死亡途径中的半胱天冬酶激活，从而能够保护前列腺癌细胞免受多种刺激诱导的细胞凋亡。
Androgen plays a critical role in the promotion and growth of prostate cancer. Androgen ablation has an expanding role in prostate cancer treatment and is now used to improve the efficacy of radiation therapy in addition to its role in treatment of metastatic disease. Here we show that androgen interferes with induction of prostate cancer cell death induced by a variety of stimuli. The effect of androgen on cell death occurs predominantly by interference with caspase activation and the inhibition of caspase cleavage in both the extrinsic and intrinsic cell death pathways. Androgen inhibited apoptosis induced by both tumor necrosis factor alpha (TNF-alpha) and by Fas activation with or without concomitant irradiation. An antiapoptotic effect was seen in the presence of R1881, dihydrotestosterone, and also 17beta-estradiol within 24 h of death induction. Sustained inhibition of apoptosis at 72 h was seen only with R1881, dihydrotestosterone, cyproterone acetate, and hydroxyflutamide. Androgen treatment inhibited activation of caspases-8, -7, and -9 by TNF-alpha +/- irradiation. Androgen attenuated BAX expression and blocked appearance of the proapoptotic p18 fragment of BAX. Androgen also abrogated BID cleavage induced by TNF-alpha + irradiation that contributed to a decrease in cytochrome c egress from mitochondria induced by TNF-alpha +/- irradiation. There was also decreased mitochondrial depolarization in response to TNF-alpha + irradiation. Production of the proapoptotic lipid metabolite ceramide was not affected by androgen, but androgen acted downstream from ceramide generation because R1881 blocked cell-death induction by bacterial sphingomyelinase. Inhibition of phosphoinositol-3-kinase activity by wortmannin induced apoptosis that was also blocked by androgen, but there was no effect on protein levels or phosphorylation of AKT, indicating that R1881 did not interact with survival signaling of phosphoinositol-3-kinase. Lastly, androgen inhibited activation of nuclear factor-kappaB during death induction, but the effect of androgen on cell death was not mediated by interference with the nuclear factor-kappaB pathway. The data suggest that androgen induced blockade of caspase activation in both intrinsic and extrinsic cell death pathways and thereby was able to protect prostate cancer cells from apoptosis induced by diverse stimuli.