Bcl-2 overexpression results in reciprocal downregulation of Bcl-XL and sensitizes human testicular germ cell tumours to chemotherapy-induced apoptosis
Bcl-2 overexpression results in reciprocal downregulation of Bcl-XL and sensitizes human testicular germ cell tumours to chemotherapy-induced apoptosis
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DOI：
10.1038/sj.onc.1202420
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发表时间：
1999-02-18
期刊：
影响因子：
8
通讯作者：
Chresta, CM
中科院分区：
文献类型：
--
作者：
Arriola, EL;Rodriguez-Lopez, AM;Chresta, CM
睾丸生殖细胞肿瘤对化学疗法高度敏感，并且源自这些肿瘤的细胞系在体外是化学敏感的。我们先前已经表明，这些细胞系表达不可检测水平的凋亡抑制因子Bcl-2和相对高水平的凋亡诱导因子Bar（Chresta等人，1996年）。为了确定这些细胞系中Bcl-2的缺乏是否使它们对药物诱导的细胞凋亡高度敏感，在833 K睾丸生殖细胞肿瘤细胞系中异位表达Bcl-2。分离稳定的过表达克隆，并进一步研究三个克隆。令人惊讶的是，与亲本和载体对照细胞相比，Eel-2过表达细胞对化疗诱导的细胞凋亡敏感。潜在的致敏机制的分析表明，有相互下调的内源性表达的Bcl-X-L的鳗鱼2过表达克隆。反义寡核苷酸下调Bcl-X-L至相同程度可使依托泊苷诱导的细胞凋亡增加两倍。我们的研究结果表明，Eel-2和Bcl-X-L有不同的能力，以防止化疗诱导的睾丸生殖细胞肿瘤细胞凋亡。与某些肿瘤细胞类型中的发现相反，Eel-2并不作为阻止p53进入细胞核的看门人。
Testicular germ cell tumours are hypersentive to chemotherapy and cell lines derived from these tumours are chemosensitive in vitro. We have previously shown that these cell lines express undetectable levels of the suppressor of apoptosis Bcl-2 and relatively high levels of the apoptosis inducer Bar (Chresta et al., 1996). To determine whether the absence of Bcl-2 in these cell lines makes them highly susceptible to drug-induced apoptosis, Bcl-2 was expressed ectopically in the 833K testicular germ cell tumour cell line. Stable overexpressing clones were isolated and three clones were studied further. Surprisingly, Eel-2 overexpressing cells were sensitized to chemotherapy-induced apoptosis compared to the parental and vector control cells. Analysis of potential mechanisms of sensitization revealed there was reciprocal downregulation of the endogenously expressed Bcl-X-L in the Eel-2 overexpressing clones. Downregulation of Bcl-X-L to the same extent using antisense oligonucleotides enhanced etoposide-induced apoptosis by twofold. Our results indicate that Eel-2 and Bcl-X-L have different abilities to protect against chemotherapy-induced apoptosis in testicular germ cell tumours. In contrast to findings in some tumour cell types, Eel-2 did not act as a gatekeeper to prevent entry of p53 to the nucleus.