抑制 NADPH 氧化酶调节慢性髓性白血病中血红素加氧酶 1 的表达。
Inhibition of the NADPH oxidase regulates heme oxygenase 1 expression in chronic myeloid leukemia.
机构信息
Department of Pediatrics Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
出版信息
Cancer. 2012 Jul 1;118(13):3433-45. doi: 10.1002/cncr.26621. Epub 2011 Dec 2.
BACKGROUND
Patients with chronic myelogenous leukemia (CML) in blast crisis have a poor response to tyrosine kinase inhibitors designed to inhibit the breakpoint cluster region-v-Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL1) oncogene. Recent work has demonstrated that heme oxygenase 1 (HO-1) expression is increased in BCR-ABL1-expressing cells and that the inhibition of HO-1 in CML leads to reduced cellular growth, suggesting that HO-1 may be a plausible target for therapy. The objective of the current study was to clarify the mechanism of HO-1 overexpression and the role of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase as a contributor to this mechanism in CML.
METHODS
HO-1 expression was evaluated in bone marrow specimens from patients with CML in various stages of disease, in a transplantation-based model for CML, and in CML cell lines. Chemical and genetic inhibition of the NADPH oxidase was carried out in CML cells.
RESULTS
Specimens from patients with CML in blast crisis displayed higher levels of HO-1 staining than specimens from patients with CML in chronic or accelerated phase. HO-1 up-regulation in BCR-ABL1-expressing cells was suppressed by diphenyleneiodonium (DPI), a chemical inhibitor of the NADPH oxidase. Targeting the NADPH oxidase through RNA interference (RNAi) to Ras-related C3 botulinum toxin substrate 1 (Rac1), a dominant-negative Rac1 construct or an inhibitor of Rac1 activity also blunted HO-1 protein expression. Moreover, inhibition of the NADPH oxidase by RNAi directed toward the 47-kd cytosolic subunit of Nox (p47phox) similarly abrogated HO-1 levels.
CONCLUSIONS
BCR-ABL1 expression up-regulated HO-1, a survival factor for CML cells. This up-regulation was more pronounced in blast crisis CML relative to early stage disease and was mediated by the NADPH oxidase components Rac1 and p47phox. The expression of p47phox was increased in BCR-ABL1-expressing cells.
背景
慢性髓性白血病（CML）处于爆发期的患者对旨在抑制断裂点簇区-ABL 白血病病毒致癌基因同源物 1（BCR-ABL1）癌基因的酪氨酸激酶抑制剂反应不佳。最近的研究表明，血红素加氧酶 1（HO-1）在表达 BCR-ABL1 的细胞中表达增加，并且在 CML 中抑制 HO-1 可导致细胞生长减少，这表明 HO-1 可能是一种合理的治疗靶标。本研究的目的是阐明 HO-1 过表达的机制，以及烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶作为该机制在 CML 中的贡献者的作用。
方法
评估了来自处于疾病各个阶段的 CML 患者的骨髓标本、CML 移植模型和 CML 细胞系中的 HO-1 表达。对 CML 细胞中的 NADPH 氧化酶进行了化学和遗传抑制。
结果
爆发期 CML 患者的标本比慢性期或加速期 CML 患者的标本显示出更高水平的 HO-1 染色。BCR-ABL1 表达细胞中 HO-1 的上调被二苯并碘（DPI）抑制，DPI 是 NADPH 氧化酶的化学抑制剂。通过 RNA 干扰（RNAi）靶向 NADPH 氧化酶的 Ras 相关 C3 肉毒杆菌毒素底物 1（Rac1）、显性负 Rac1 构建体或 Rac1 活性抑制剂也使 HO-1 蛋白表达减弱。此外，针对 Nox 的 47kD 细胞质亚基（p47phox）的 RNAi 抑制同样消除了 HO-1 水平。
结论
BCR-ABL1 表达上调了 HO-1，这是 CML 细胞的生存因子。与早期疾病相比，爆发期 CML 中这种上调更为明显，并且由 NADPH 氧化酶成分 Rac1 和 p47phox 介导。BCR-ABL1 表达细胞中 p47phox 的表达增加。
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