Id-1 regulates Bcl-2 and Bax expression through p53 and NF-κB in MCF-7 breast cancer cells
Id-1 regulates Bcl-2 and Bax expression through p53 and NF-κB in MCF-7 breast cancer cells
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DOI：
10.1007/s10549-007-9871-6
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发表时间：
2008-11-01
影响因子：
3.8
通讯作者：
Kong, Gu
中科院分区：
文献类型：
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作者：
Kim, Hwan;Chung, Heekyoung;Kong, Gu
尽管越来越多的证据支持分化抑制剂和DNA结合-1 （Id-1）对抗癌药物诱导的细胞凋亡的保护作用，但其潜在的分子机制似乎因肿瘤系统而异。在这里，我们通过在无血清条件下异位过表达Id-1来检测Id-1在MCF-7乳腺癌细胞中的直接作用，在无血清条件下，内源性Id-1表达被抑制。表达Id-1导致活细胞数增加，Bax表达降低，Bcl-2表达增强，但Bcl-xL表达无变化。核因子κ B （nf - κ B）表达增强，而p53和I κ B表达降低。通过实时聚合酶链反应和对其已知下游靶标p21和Il-6以及Bax和Bcl-2基因的报告基因测定来评估，p53和NF-kappa B通路的这种变化也是功能性的。最后，在紫杉醇处理（0-200 nM）时，通过MTT试验和凋亡细胞计数评估Id-1对紫杉醇诱导的乳腺癌细胞凋亡具有保护作用。在紫杉醇的作用下，细胞中Bax的表达减少，Bcl-2的表达增加。综上所述，我们提出了一种分子机制，其中Id-1调节p53和NF-kappa B通路，进而调节Bax和Bcl-2基因，从而在外源应激（如无血清或紫杉醇处理）下为MCF-7乳腺癌细胞提供生存优势。在这方面，Id-1的失活可能提供一种潜在的治疗策略，可以抑制乳腺癌的进展和抗癌耐药性。
Although increasing evidence supports the protective role of inhibitor of differentiation and DNA binding-1 (Id-1) against anticancer drug-induced apoptosis, the underlying molecular mechanisms seem to vary depending on the tumor system. Here, we examined the direct role of Id-1 in MCF-7 breast cancer cells by ectopically overexpressing Id-1 under serum-free condition, where the endogenous Id-1 expression was suppressed. Id-1 expression resulted in increased number of viable cells, reduced Bax expression, enhanced Bcl-2 expression, but no change in Bcl-xL expression. The expression of nuclear factor-kappa B (NF-kappa B) was augmented, while those of p53 and I kappa B were reduced. Such changes in p53 and NF-kappa B pathways were also functional, as assessed by real-time polymerase chain reactions and reporter assays of their known downstream targets, p21 and Il-6, as well as Bax and Bcl-2 genes. Finally, Id-1 played a protective role against taxol-induced apoptosis in breast cancer cells as assessed by MTT assay and apoptotic cell count upon taxol treatment (0-200 nM). Reduced Bax expression and enhanced Bcl-2 expression by Id-1 were also noted in the presence of taxol. Taken together, we present a molecular mechanism where Id-1 regulates p53 and NF-kappa B pathways, which in turn regulates Bax and Bcl-2 genes, thus providing a survival advantage under exogenous stress such as serum-free or taxol treatment in MCF-7 breast cancer cells. In this regard, inactivation of Id-1 may provide a potential therapeutic strategy leading to inhibition of breast cancer progression and anti-cancer drug resistance.