BCL6 overexpression prevents increase in reactive oxygen species and inhibits apoptosis induced by chemotherapeutic reagents in B-cell lymphoma cells
BCL6 overexpression prevents increase in reactive oxygen species and inhibits apoptosis induced by chemotherapeutic reagents in B-cell lymphoma cells
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DOI：
10.1038/sj.onc.1206755
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发表时间：
2003-07-17
期刊：
影响因子：
8
通讯作者：
Miura, O
中科院分区：
文献类型：
--
作者：
Kurosu, T;Fukuda, T;Miura, O
染色体易位和体细胞突变发生在BCL 6基因的5'非编码区，编码转录抑制因子，是与非霍奇金B细胞淋巴瘤相关的最常见的遗传异常，并导致BCL 6的表达失调。然而，BCL 6的表达失调在淋巴瘤发生中的意义及其对淋巴瘤患者临床结局的影响仍然难以捉摸。在本研究中，我们建立了Daudi和Raji B细胞淋巴瘤细胞系，过度表达BCL 6或其突变体BCL 6-Ala 333/343，其中通过B细胞受体刺激细胞中的蛋白酶体途径降解所需的丝氨酸残基发生突变。BCL 6过表达对细胞增殖没有任何显著影响，但显著抑制由依托泊苷引起的凋亡，依托泊苷诱导BCL 6的蛋白酶体依赖性降解。BCL 6-Ala 333/343在依托泊苷处理后不降解，并强烈抑制凋亡。在这些淋巴瘤细胞系中，依托泊苷增加了活性氧（ROS）的产生，降低了线粒体膜电位，这两者都被抗氧化剂N-乙酰-L-半胱氨酸（NAC）抑制。NAC也抑制细胞凋亡。此外，发现BCL 6过表达抑制ROS水平的增加和细胞凋亡对依托泊苷和其他化疗试剂的响应。这些结果提高了BCL 6表达失调可能赋予淋巴瘤细胞对化疗试剂的抗性的可能性，最有可能是通过增强抗氧化防御系统。
Chromosomal translocations and somatic mutations occurring in the 5' noncoding region of the BCL6 gene, encoding a transcriptional repressor, are most frequent genetic abnormalities associated with non-Hodgkin B-cell lymphoma and result in deregulated expression of BCL6. However, the significance of deregulated expression of BCL6 in lymphomagenesis and its effect on clinical outcomes of lymphoma patients have remained elusive. In the present study, we established Daudi and Raji B-cell lymphoma cell lines that overexpress BCL6 or its mutant, BCL6-Ala333/343, in which serine residues required for degradation through the proteasome pathway in B-cell receptor-stimulated cells are mutated. BCL6 overexpression did not have any significant effect on cell proliferation, but significantly inhibited apoptosis caused by etoposide, which induced a proteasome-dependent degradation of BCL6. BCL6-Ala333/343 was not degraded after etoposide treatment and strongly inhibited apoptosis. In these lymphoma cell lines, etoposide increased the generation of reactive oxygen species (ROS) and reduced mitochondria membrane potential, both of which were inhibited by the antioxidant N-acetyl-L-cysteine (NAC). NAC also inhibited apoptosis. Furthermore, BCL6 overexpression was found to inhibit the increase in ROS levels and apoptosis in response to etoposide and other chemotherapeutic reagents. These results raise the possibility that deregulated expression of BCL6 may endow lymphoma cells with resistance to chemotherapeutic reagents, most likely by enhancing the antioxidant defense systems.