Inhibition of apoptosis by downregulation of hBex1, a novel mechanism, contributes to the chemoresistance of Bcr/Abl+ leukemic cells
Inhibition of apoptosis by downregulation of hBex1, a novel mechanism, contributes to the chemoresistance of Bcr/Abl+ leukemic cells
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通过下调 hBex1 抑制细胞凋亡是一种新机制，有助于 Bcr/Abl 白血病细胞的化疗耐药
DOI：
10.1093/carcin/bgn251
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发表时间：
2009-01-01
期刊：
影响因子：
4.7
通讯作者：
Zhu, Yongliang
中科院分区：
文献类型：
--
作者：
Ding, Kefeng;Su, Yanyan;Zhu, Yongliang
多药耐药蛋白（multidrug resistance proteins，Mdrs）的过度表达和抗凋亡能力的增强是Bcr/Abl（+）慢性髓系白血病细胞获得耐药的两个主要机制，然而，已有研究表明Mdr 1的表达对化疗药物诱导的细胞凋亡的保护作用微乎其微。细胞在耐药过程中获得增强的抗凋亡能力的机制需要进一步了解。在这里，我们确定人脑表达的X-连锁1（hBex 1）作为p75神经营养因子受体通路的下游靶点在伊马替尼耐药K562细胞通过比较基因表达谱与亲本K562细胞。沉默hBex 1抑制伊马替尼诱导的细胞凋亡和hBex 1致敏细胞对伊马替尼诱导的细胞凋亡的过度表达。进一步的研究发现hBex 1与原钙粘蛋白10（protocadherin 10，PCDH 10）相关。pcdh 10的沉默减弱了伊马替尼诱导的hBex 1转染细胞的凋亡，这表明，除了Mdr和Bcl-2家族成员，hBex 1的表达减少也可以抑制伊马替尼诱导的凋亡。这些数据提供的证据表明，hBex 1在白血病细胞中的表达是一种新的机制，通过这种机制实现化疗耐药性，并表明hBex 1是一个潜在的分子靶点，用于开发新的白血病治疗。
Overexpression of multidrug resistance proteins (Mdrs) and enhanced antiapoptotic capability are two of the main mechanisms by which Bcr/Abl(+) chronic myeloid leukemia cells acquire drug resistance; however, it has been shown that Mdr-1 expression provides minimal protection against cell apoptosis induced by chemotherapeutic drugs. The mechanism by which cells acquire an enhanced antiapoptosis capacity in the drug-resistant process needs to be further understood. Here, we identified human brain expressed X-linked 1 (hBex1) as a downstream target of the p75 neurotrophin receptor pathway in imatinib-resistant K562 cells by comparing the gene expression profiles with the parent K562 cells. Silencing hBex1 inhibited imatinib-induced cell apoptosis and overexpression of hBex1-sensitized cells to imatinib-induced apoptosis. Further investigation revealed that hBex1 associates with protocadherin 10 (PCDH10). Silencing of pcdh10 attenuated apoptosis induced by imatinib in hBex1 transfected cells, suggesting that, in addition to Mdr and Bcl-2 family members, reduced expression of hBex1 can also inhibit imatinib-induced apoptosis. These data provide evidence that expression of hBex1 in leukemic cells is a novel mechanism by which chemoresistance is achieved and suggests that hBex1 is a potential molecular target for the development of novel leukemia treatments.