Resistance to chemotherapy via Stat3-dependent overexpression of Bcl-2 in metastatic breast cancer cells
Resistance to chemotherapy via Stat3-dependent overexpression of Bcl-2 in metastatic breast cancer cells
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DOI：
10.1038/sj.onc.1206004
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发表时间：
2002-10-31
期刊：
影响因子：
8
通讯作者：
Fernandez-Luna, JL
中科院分区：
文献类型：
--
作者：
Real, PJ;Sierra, A;Fernandez-Luna, JL
阻断细胞凋亡可能会使转移细胞存活，并使其对化疗药物产生耐药性。我们已经分析了在特定的转移部位激活这些生存基因的分子途径。对雌激素受体阴性的乳腺癌细胞株MDA-MB435以及肺(435L)和脑(435B)的两个转移亚株进行了细胞凋亡调节基因Bcl2家族成员的表达分析。转移亚系细胞中Bcl2的表达水平高于亲代细胞，其表达水平与STAT3的活化有关，而与已知的bcl2转录因子(CREB和WT1)的表达和/或激活无关。在脑亚系中，Bcl2的表达和STAT3的激活都是由表皮生长因子诱导的，而用表皮生长因子受体特异性的激酶抑制剂或JAK2处理后则被抑制。此外，在亲代435细胞中，转导显性负性STAT3的435B显著降低了Bcl2蛋白的表达，而瞬时表达活性STAT3则增加了Bcl2的表达。此外，用表皮生长因子受体和JAK2激酶抑制剂处理或用显性阴性的STAT3基因转染来阻断STAT3的激活，会使435B细胞对化疗诱导的细胞凋亡变得敏感。我们的数据表明，在雌激素受体阴性的转移性乳腺癌细胞系中，STAT3-Bcl2通路的激活增加为这些细胞提供了生存优势，并导致了它们的化疗耐药。
Disruption of apoptosis may allow metastatic cell survival and confer resistance to chemotherapeutic drugs. We have analysed the molecular pathways that activate these survival genes in specific sites of metastasis. Estrogen receptor-negative breast cancer cell line MDA-MB435 and two metastatic sublines derived from lung (435L) and brain (435B) were analysed for the expression of members of the Bcl-2 family of apoptosis regulators. The levels of Bcl-2 were higher in the metastatic sublines than in parental cells, which correlated with the activation of Stat3, but not with the expression and/or activation of known bcl-2 transcription factors (CREB and WT1). In the brain subline, both expression of Bcl-2 and Stat3 activation were induced by epidermal growth factor and abrogated after treatment with kinase inhibitors specific for epidermal growth factor receptor or Jak2. Furthermore, transfection of 435B with a dominant-negative Stat3 markedly reduced the expression of Bcl-2 protein, whereas transient expression of a constitutively active Stat3 increased Bcl-2 in parental 435 cells. In addition, blockade of Stat3 activation by treatment with epidermal growth factor receptor and Jak2 kinase inhibitors or transfection with a dominant negative Stat3, sensitizes 435B cells to chemotherapy-induced apoptosis. Our data suggest that an increased activation of the Stat3-Bcl-2 pathway in estrogen receptor-negative metastatic breast cancer cell lines confer a survival advantage to these cells and contribute to their chemoresistance.