Bcl-xL is overexpressed in hormone-resistant prostate cancer and promotes survival of LNCaP cells via interaction with proapoptotic Bak
Bcl-xL is overexpressed in hormone-resistant prostate cancer and promotes survival of LNCaP cells via interaction with proapoptotic Bak
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DOI：
10.1210/en.2006-0502
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发表时间：
2006-10-01
期刊：
影响因子：
4.8
通讯作者：
Saez, Carmen
中科院分区：
文献类型：
--
作者：
Castilla, Carolina;Congregado, Belen;Saez, Carmen
雄激素敏感性前列腺癌细胞通过涉及细胞凋亡失调的复杂机制转变为雄激素抵抗。我们研究了抗凋亡Bcl-xL在前列腺癌进展中的作用，以及Bcl-xL与促凋亡Bax和巴克在雄激素依赖性和非依赖性前列腺癌细胞中的相互作用。应用免疫组化方法检测139例前列腺癌组织中Bcl-xL的表达，并分析其与Gleason分级和激素抵抗时间的关系。Bcl-xL的表达在Gleason分级较高的前列腺癌中更丰富，并且与前列腺癌难治性疾病的发生显著相关。用免疫共沉淀法研究了Bcl-xL与Bax或巴克在未经处理和经喜树碱处理的LNCaP和PC 3细胞中的相互作用。在没有任何刺激的情况下，Bcl-xL在雄激素非依赖性PC 3细胞中与Bax和巴克相互作用，但在雄激素依赖性LNCaP细胞中仅与巴克相互作用。Bcl-xL与Bax和巴克的相互作用也在来自高级别前列腺癌组织的裂解物中得到证实。拓扑异构酶I抑制剂喜树碱处理LNCaP细胞36 h后，Bcl-xL与巴克之间的相互作用消失，Bcl-xL逐渐减少，巴克逐渐增加。这些结果支持Bcl-xL通过异源二聚化对巴克发挥抑制作用的模型。我们认为这些相互作用可能提供了抑制前列腺癌细胞中促凋亡Bax和巴克活性的机制，并且Bcl-xL表达有助于雄激素抵抗和前列腺癌的进展。
Androgen-sensitive prostate cancer cells turn androgen resistant through complex mechanisms that involve dysregulation of apoptosis. We investigated the role of antiapoptotic Bcl-xL in the progression of prostate cancer as well as the interactions of Bcl-xL with proapoptotic Bax and Bak in androgen-dependent and -independent prostate cancer cells. Immunohistochemical analysis was used to study the expression of Bcl-xL in a series of 139 prostate carcinomas and its association with Gleason grade and time to hormone resistance. Expression of Bcl-xL was more abundant in prostate carcinomas of higher Gleason grades and significantly associated with the onset of hormone-refractory disease. In vivo interactions of Bcl-xL with Bax or Bak in untreated and camptothecin-treated LNCaP and PC3 cells were investigated by means of coimmunoprecipitation. In the absence of any stimuli, Bcl-xL interacts with Bax and Bak in androgen-independent PC3 cells but only with Bak in androgen-dependent LNCaP cells. Interactions of Bcl-xL with Bax and Bak were also evidenced in lysates from high-grade prostate cancer tissues. In LNCaP cells treated with camptothecin, an inhibitor of topoisomerase I, the interaction between Bcl-xL and Bak was absent after 36 h, Bcl-xL decreased gradually and Bak increased coincidentally with the progress of apoptosis. These results support a model in which Bcl-xL would exert an inhibitory effect over Bak via heterodimerization. We propose that these interactions may provide mechanisms for suppressing the activity of proapoptotic Bax and Bak in prostate cancer cells and that Bcl-xL expression contributes to androgen resistance and progression of prostate cancer.