Institut de Recherche Thérapeutique de l'Université de Nantes, Equipe 10 labellisée Ligue Nationale contre le Cancer 2008, 8 quai Moncousu, Nantes BP70721 F-44007, France.
Br J Cancer. 2010 Dec 7;103(12):1808-14. doi: 10.1038/sj.bjc.6605981. Epub 2010 Nov 9.
although gene expression profile of multiple myeloma (MM) patients shows a wide range of Bik/Nbk expression, varying from absent to high, its regulation and function in myeloma cells is poorly understood. Thus, we addressed these questions in MM.
human myeloma cell lines (HMCLs) and primary purified myeloma cells were studied for Bcl-2 family protein expression by western blot and further correlation analysis was performed. Correlative study between Bik and thyrotroph embryonic factor (TEF) transcription factor expression was analysed by PCR. Stress oxidative response was analysed by flow cytometry.
a strong expression of Bik protein was found only in one out of three of HMCL and correlated to Bcl-2 expression (P=0.0006). We demonstrated that Bik could be regulated at the protein level by Bcl-2 and at the transcriptional level by TEF. Bik overexpression sensitises myeloma cells to oxidative stress whereas Bik silencing increases resistance to H(2)O(2) oxidative stress. Furthermore, Bik ectopic expression disrupts Bim/Bcl-2 and Bim/Bcl-xL endogenous complexes triggering Bim release that could induce Bax and Bak activation.
ours results suggest that Bik has a role in both, apoptosis induction and sensitivity to oxidative stress in myeloma cells. Small BH3 mimetic molecules should be considered for further apoptosis-based therapy in myeloma cells expressing endogenous Bik/Bcl-2 complexes.
尽管多发性骨髓瘤（MM）患者的基因表达谱显示 Bik/Nbk 表达范围广泛，从缺失到高表达不等，但它在骨髓瘤细胞中的调节和功能仍知之甚少。因此，我们在 MM 中研究了这些问题。
通过 Western blot 研究了人骨髓瘤细胞系（HMCL）和原代纯化骨髓瘤细胞中 Bcl-2 家族蛋白的表达，并进行了进一步的相关性分析。通过 PCR 分析了 Bik 和甲状腺激素胚胎因子（TEF）转录因子表达之间的相关性。通过流式细胞术分析应激氧化反应。
只有在 3 个 HMCL 中的 1 个中发现 Bik 蛋白表达强烈，与 Bcl-2 表达相关（P=0.0006）。我们证明 Bik 可以在蛋白水平上被 Bcl-2 调节，在转录水平上被 TEF 调节。Bik 的过表达使骨髓瘤细胞对氧化应激敏感，而 Bik 沉默增加了对 H2O2 氧化应激的抵抗力。此外，Bik 异位表达破坏了 Bim/Bcl-2 和 Bim/Bcl-xL 内源性复合物，引发 Bim 释放，从而诱导 Bax 和 Bak 的激活。
我们的结果表明，Bik 在骨髓瘤细胞的凋亡诱导和对氧化应激的敏感性中都发挥作用。在表达内源性 Bik/Bcl-2 复合物的骨髓瘤细胞中，应考虑使用小分子 BH3 模拟物进行进一步的基于凋亡的治疗。
