Acute hypoxia increases the aggressive characteristics and survival properties of prostate cancer cells
Acute hypoxia increases the aggressive characteristics and survival properties of prostate cancer cells
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DOI：
10.1002/pros.10162
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发表时间：
2003-01-01
期刊：
影响因子：
2.8
通讯作者：
Buttyan, R
中科院分区：
文献类型：
--
作者：
Ghafar, MA;Anastasiadis, AG;Buttyan, R
背景。雄激素撤除是晚期前列腺癌的标准治疗策略，会导致流向前列腺和前列腺癌组织的血流迅速减少，并伴随这些组织中出现缺氧环境。为了确定缺氧反应性（通过缺氧诱导因子 [HIF] -1α 蛋白的作用）是否可能影响前列腺癌细胞的致瘤或存活特性，我们研究了培养的人前列腺癌细胞（LNCaP 细胞系）急性暴露于缺氧可能如何改变其基因表达模式及其体外行为。 LNCaP 培养物置于缺氧室中培养 24 小时，并通过蛋白质印迹和半定量逆转录聚合酶链式反应技术与对照（常氧）细胞比较基因产物的表达。结果。 LNCaP 细胞暴露于急性缺氧会激活典型的细胞缺氧反应，其特征是 HIF-1α 和血管内皮生长因子蛋白表达上调。相反，分化特异性蛋白（前列腺特异性抗原和雄激素受体）或增殖调节蛋白（c-myc、细胞周期蛋白D1、p27）的表达因缺氧而下调。后面的一些变化（c-myc 和细胞周期蛋白 D 表达的减少）并不伴随相应的 mRNA 减少，而是被蛋白酶体抑制剂 (MG132) 消除，这表明它们的损失与其降解增加有关，而不是通过转录控制。 Akt/蛋白激酶 B 及其下游靶标叉头蛋白的磷酸化因缺氧而高度上调，与常氧细胞相比，暴露于短暂缺氧的细胞对凋亡刺激（暴露于佛波酯）的敏感性显着降低。结论。这项研究表明，即使是急性缺氧也有可能彻底改变前列腺癌细胞的生长、分化特征和凋亡敏感性。 (C) 2002 Wiley-Liss, Inc.
BACKGROUND. Androgen withdrawal, the standard therapeutic strategy for advanced prostate cancer, induces a rapid reduction of blood flow to prostate and prostate cancer tissues and the concomitant onset of a hypoxic environment in these tissues. To establish whether hypoxia-responsiveness (by means of the action of hypoxia inducible factor [HIF] -1alpha protein) might affect the tumorigenic or survival properties of prostate cancer cells, we studied how acute exposure of cultured human prostate cancer cells (LNCaP cell line) to hypoxia might alter their pattern of gene expression and their in vitro behavior,METHODS. LNCaP cultures were placed in a hypoxia chamber for Lip to 24 hr and were compared with control (normoxic) cells for the expression of gene products by Western blotting and semiquantitative reverse transcription-polymerase chain reaction techniques.RESULTS. Exposure of LNCaP cells to acute hypoxia activated a typical Cellular hypoxia response characterized by up-regulation of HIF-1alpha and vascular endothelial growth factor protein expression. In contrast, expression of differentiation-specific proteins (prostate specific antigen and androgen receptor) or proliferative-regulatory proteins (c-myc, cyclin D1, p27) were down-regulated by hypoxia. Some of these latter changes (reduction of c-myc and cyclin D expression) were not accompanied by corresponding reduction of mRNAs and were abrogated by a proteosome inhibitor (MG132), suggesting that their loss was associated with their increased degradation rather than through transcriptional controls. The phosphorylation of Akt/protein kinase B and its downstream target, forkhead protein, was highly up-regulated by hypoxia, and cells exposed to transient periods of hypoxia became significantly less sensitive to an apoptotic stimulus (exposure to phorbol ester) when compared with normoxic cells.CONCLUSION. This study demonstrates that even acute hypoxia has the potential to drastically alter the growth, differentiation characteristics, and apoptotic sensitivity of a prostate cancer cell. (C) 2002 Wiley-Liss, Inc.