Bcl-2 oncoprotein blocks chemotherapy-induced apoptosis in a human leukemia cell line.
Bcl-2 oncoprotein blocks chemotherapy-induced apoptosis in a human leukemia cell line.
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DOI：
10.1182/blood.v81.1.151.bloodjournal811151
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发表时间：
1993-01
期刊：
影响因子：
20.3
通讯作者：
T. Miyashita;John Calvin Reed
中科院分区：
文献类型：
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作者：
T. Miyashita;John Calvin Reed
以前的研究表明，bcl-2基因编码的线粒体蛋白，主要通过干扰“程序性细胞死亡”（PCD），也称为“凋亡”，促进细胞存活，从而促进肿瘤细胞的扩增。“由于许多化疗药物能够启动导致细胞凋亡的途径，我们确定了bcl-2表达失调是否会使细胞对几种常用于治疗非霍奇金淋巴瘤的药物产生耐药性，这些药物包括地塞米松（DEX）、甲氨蝶呤（MTX）、1-β-D-阿拉伯呋喃糖基胞嘧啶（Ara-C）、依托泊苷（VP-16）、长春新碱（VC）、顺铂（CP）、和氢过氧环磷酰胺（4-HC）。对于这些实验，我们实现了高水平的p26-Bcl-2蛋白生产的人前B细胞白血病细胞系697稳定感染重组bcl-2的逆转录病毒，然后比较这些细胞与对照病毒感染的697细胞。对照697细胞被所有测试药物诱导经历细胞凋亡，如通过DNA降解成寡核小体长度片段、细胞收缩和随后的细胞死亡所定义的。与此相反，697细胞与Bcl-2蛋白水平升高表现出显着延长的细胞存活率和显着减少DNA片段化时，在这些抑制剂的存在下培养。虽然高水平的Bcl-2蛋白保护697细胞免受DEX和其他测试药物的急性细胞毒性作用，但Bcl-2不能阻止这些药物抑制697细胞的增殖。然而，当697细胞用DEX或MTX处理3天，然后洗涤并在不含药物的半固体培养基中培养时，bcl-2病毒感染的细胞比用对照病毒稳定感染的697细胞以高得多的频率产生集落。这些结果表明，通过保护697白血病细胞免受DEX和一些其他化疗药物的急性细胞毒性，高水平的p26-Bcl-2可以在药物被撤回时创造重新启动细胞生长的机会。这些发现可能与非霍奇金淋巴瘤患者的临床相关研究有关，这些研究发现了预后不良与bcl-2基因重排或t[14;18]易位之间的关联。
Previous studies have shown that the bcl-2 gene encodes a mitochondrial protein that contributes to neoplastic cell expansion primarily by promoting cell survival through interference with "programmed cell death" (PCD), also termed "apoptosis." Because many chemotherapeutic drugs are capable of initiating pathways leading to apoptosis, we determined whether deregulated bcl-2 expression could render cells resistant to several drugs commonly used in the treatment of non-Hodgkin's lymphomas, including dexamethasone (DEX), methotrexate (MTX), 1-beta-D-arabinofuranosyl-cytosine (Ara-C), etoposide (VP-16), vincristine (VC), cisplatin (CP), and hydroperoxycyclophosphamide (4-HC). For these experiments, we achieved high levels of p26-Bcl-2 protein production in a human pre-B-cell leukemia line 697 by stable infection with a recombinant bcl-2-containing retrovirus and then compared these cells with control virus-infected 697 cells. Control 697 cells were induced to undergo apoptosis by all drugs tested as defined by DNA degradation into oligonucleosomal-length fragments, cell shrinkage, and subsequent cell death. In contrast, 697 cells with elevated Bcl-2 protein levels exhibited strikingly prolonged cell survival and markedly reduced DNA fragmentation when cultured in the presence of these antineoplastic agents. Although high levels of Bcl-2 protein protected 697 cells from the acute cytotoxic effects of DEX and the other drugs tested, Bcl-2 did not prevent these drugs from suppressing the proliferation of 697 cells. However, when 697 cells were treated with DEX or MTX for 3 days, then washed and cultured in semisolid media without drugs, bcl-2-virus-infected cells gave rise to colonies at much higher frequencies than 697 cells stably infected with control virus. These results indicate that by protecting 697 leukemic cells from the acute cytotoxicity of DEX and some other chemotherapeutic drugs, high levels of p26-Bcl-2 can create the opportunity for re-initiation of cell growth when drugs are withdrawn. The findings may be relevant to clinical correlative studies of non-Hodgkin's lymphoma patients that have found an association between worse prognosis and bcl-2 gene rearrangements or t[14;18] translocations.