Cancer cell sensitivity to bortezomib is associated with survivin expression and p53 status but not cancer cell types.
Cancer cell sensitivity to bortezomib is associated with survivin expression and p53 status but not cancer cell types.
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DOI：
10.1186/1756-9966-29-8
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发表时间：
2010-01-22
期刊：
影响因子：
--
通讯作者：
Li F
中科院分区：
文献类型：
--
作者：
Ling X;Calinski D;Chanan-Khan AA;Zhou M;Li F
已知生存素在耐药性中发挥作用。然而，其在硼替佐米介导的生长抑制和细胞凋亡诱导中的作用尚不清楚。关于硼替佐米对生存素表达的影响存在相互矛盾的报道，缺乏合理的解释。方法：在本研究中，我们使用 MTT 测定、流式细胞术、DNA 片段化、半胱天冬酶激活、蛋白质印迹和 RNAi 技术测试了 p53 野生型和突变/无效背景的癌细胞，以了解硼替佐米耐药性与生存素表达和 p53 状态的关系。我们发现，具有野生型p53的癌细胞表现出低水平的生存素表达，并且对硼替佐米治疗敏感，而具有突变型或无效p53的癌细胞表现出高水平的生存素表达，并且对硼替佐米介导的细胞凋亡诱导具有抵抗力。然而，在 p53 突变体或无效细胞中利用生存素 mRNA 特异性 siRNA/shRNA 沉默生存素表达，可使癌细胞对硼替佐米介导的细胞凋亡诱导敏感，表明生存素在硼替佐米耐药中发挥作用。我们进一步注意到，硼替佐米对生存素表达的调节依赖于 p53 状态，但与癌细胞类型无关。在p53突变或p53缺失的癌细胞中，硼替佐米似乎诱导生存素表达，而在野生型p53的癌细胞中，硼替佐米下调生存素表达或对生存素表达没有显着影响，这取决于药物浓度、细胞系和暴露时间。我们的研究结果首次统一了目前硼替佐米治疗和生存素表达不一致的研究结果，并将硼替佐米对生存素表达、细胞凋亡诱导和硼替佐米耐药的影响与 p53 状态联系起来，而 p53 状态与癌细胞类型无关。沿着这条线的进一步机制研究可能会影响硼替佐米在实体癌症治疗中的最佳临床应用。
Survivin is known playing a role in drug resistance. However, its role in bortezomib-mediated inhibition of growth and induction of apoptosis is unclear. There are conflicting reports for the effect of bortezomib on survivin expression, which lacks of a plausible explanation. Methods: In this study, we tested cancer cells with both p53 wild type and mutant/null background for the relationship of bortezomib resistance with survivin expression and p53 status using MTT assay, flow cytometry, DNA fragmentation, caspase activation, western blots and RNAi technology. We found that cancer cells with wild type p53 show a low level expression of survivin and are sensitive to treatment with bortezomib, while cancer cells with a mutant or null p53 show a high level expression of survivin and are resistant to bortezomib-mediated apoptosis induction. However, silencing of survivin expression utilizing survivin mRNA-specific siRNA/shRNA in p53 mutant or null cells sensitized cancer cells to bortezomib mediated apoptosis induction, suggesting a role for survivin in bortezomib resistance. We further noted that modulation of survivin expression by bortezomib is dependent on p53 status but independent of cancer cell types. In cancer cells with mutated p53 or p53 null, bortezomib appears to induce survivin expression, while in cancer cells with wild type p53, bortezomib downregulates or shows no significant effect on survivin expression, which is dependent on the drug concentration, cell line and exposure time. Our findings, for the first time, unify the current inconsistent findings for bortezomib treatment and survivin expression, and linked the effect of bortezomib on survivin expression, apoptosis induction and bortezomib resistance in the relationship with p53 status, which is independent of cancer cell types. Further mechanistic studies along with this line may impact the optimal clinical application of bortezomib in solid cancer therapeutics.
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影响因子：
4.8
作者：
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4.8
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