Antisense strategy shows that Mcl-1 rather than Bcl-2 or BCI-xL is an essential survival protein of human myeloma cells
Antisense strategy shows that Mcl-1 rather than Bcl-2 or BCI-xL is an essential survival protein of human myeloma cells
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DOI：
10.1182/blood.v100.1.194
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发表时间：
2002-07-01
期刊：
影响因子：
20.3
通讯作者：
Amiot, M
中科院分区：
文献类型：
--
作者：
Derenne, S;Monia, B;Amiot, M
多发性骨髓瘤（MM）是一种浆细胞恶性肿瘤，主要发生在骨髓。由于MM细胞增殖缓慢，找到阻止其在骨髓内生长和积聚的方法似乎是必要的。本研究使用反义策略来阐明Bcl-2、BCI-x(L)和Mcl-1蛋白在骨髓瘤细胞存活中的各自作用。每一个反义寡核苷酸（ASO; Bcl-2, BCl-x(L)，或Mcl-1 ASO）通过电穿孔引入人骨髓瘤细胞系诱导相应的蛋白水平显著降低。Mcl-1 ASO在所有测试的骨髓瘤细胞系和2个原发性骨髓瘤细胞中引起活力的显著下降，而Bcl-2和Bcl-x(L) ASO均不影响骨髓瘤细胞的活力。Mcl-1 ASO处理诱导的细胞活力下降与通过破坏线粒体膜电位DeltaPsim和激活executioner caspase-3诱导凋亡有关。此外，我们已经证明白细胞介素6不能阻止Mcl-1 aso诱导的细胞凋亡。最后，虽然Bcl-2 ASO单独治疗没有效果，但它可以使骨髓瘤细胞株对地塞米松（Dex）增敏，而Bcl-x(L) ASO联合Dex仍然没有效果。尽管进行了强化化疗，MM仍然是一种无法治愈的疾病，这些结果表明Mcl-1反义策略而不是Bcl-2反义策略在MM的治疗中可能具有相当重要的意义。
Multiple myeloma (MM) is a plasma cell malignancy that occurs mainly in bone marrow. As MM cells proliferate slowly, it would seem essential to find means of preventing their growth and accumulation inside bone marrow. The present study used an antisense strategy to elucidate the respective roles of Bcl-2, BCI-x(L), and Mcl-1 proteins in myeloma cell survival. Each antisense oligonucleotide (ASO; Bcl-2, BCl-x(L), or Mcl-1 ASO) introduced into human myeloma cell lines by electroporation induced a marked reduction in the level of the corresponding protein. Mcl-1 ASO triggers an important decrease of viability in all myeloma cell lines tested and in 2 primary myeloma cells, whereas neither Bcl-2 nor Bcl-x(L) ASO affected the viability of myeloma cells. The decrease of cell viability induced by Mcl-1 ASO treatment was associated with an induction of apoptosis that occurred through the disruption of mitochondrial membrane potential DeltaPsim and the activation of executioner caspase-3. Furthermore, we have shown that interleukin 6 cannot prevent the Mcl-1 ASO-induced apoptosis. Finally, although Bcl-2 ASO treatment alone has no effect, it can sensitize myeloma cell lines to dexamethasone (Dex), whereas Bcl-x(L) ASO in combination with Dex still had no effect. As MM remains an incurable disease despite intensive chemotherapy, these results suggest that Mcl-1 antisense strategy rather than Bcl-2 antisense strategy could be of considerable importance in the treatment of MM.