Hemin reduces cellular sensitivity to imatinib and anthracyclins via Nrf2
Hemin reduces cellular sensitivity to imatinib and anthracyclins via Nrf2
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DOI：
10.1002/jcb.21659
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发表时间：
2008-05
影响因子：
4
通讯作者：
T. Nagai;S. Kikuchi;K. Ohmine;T. Miyoshi;Makiko Nakamura;T. Kondo;K. Furuyama;N. Komatsu;K. Ozawa
中科院分区：
文献类型：
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作者：
T. Nagai;S. Kikuchi;K. Ohmine;T. Miyoshi;Makiko Nakamura;T. Kondo;K. Furuyama;N. Komatsu;K. Ozawa
血红素在多种细胞功能中起着重要的生物调节作用。在这项研究中，我们检查了氯化血红素对伊马替尼和其他抗白血病试剂的细胞敏感性的影响。氯化血红素处理人BCR/ABL阳性KCL 22白血病细胞后，伊马替尼的IC 50值（即耐药性）以剂量依赖性方式增加，而BCR/ABL激酶活性无任何变化。伊马替尼诱导的细胞凋亡也被氯化血红素处理的KCL 22细胞抑制。氯化血红素处理增加了γ-谷氨酰半胱氨酸合成酶（γ-GCS）轻亚基基因启动子的活性，该启动子含有Maf识别元件（MARE）。氯化血红素治疗后，γ-GCS和血红素加氧酶-1（HO-1）（两种含MARE基因）的蛋白水平也升高。通过RNA干扰敲低Nrf 2表达在很大程度上消除了氯化血红素对伊马替尼处理细胞的影响，表明MARE的Nrf 2识别对于氯化血红素介导的保护作用至关重要。与氯化高铁血红素类似，用专性血红素前体δ-氨基乙酰丙酸（δ-ALA）处理细胞也会增加伊马替尼的IC 50值。相比之下，琥珀酰丙酮抑制细胞血红素合成增加了两种伊马替尼耐药细胞系KCL 22/SR和KU 812/SR中细胞对伊马替尼的敏感性。氯化血红素处理还降低了BCR/ABL阴性白血病U937和THP-1细胞以及KCL 22细胞中细胞对四种蒽环类药物（柔红霉素、伊达比星、多柔比星和米托蒽醌）的敏感性。因此，这些发现表明，细胞血红素水平在决定细胞对伊马替尼和某些其他抗白血病药物的敏感性方面起着重要作用，血红素的作用可能是通过其上调Nrf 2活性的能力介导的。J.细胞。104：680-691，2008.© 2008 Wiley利斯公司
Heme plays an important biomodulating role in various cell functions. In this study, we examined the effects of hemin on cellular sensitivity to imatinib and other anti‐leukemia reagents. Hemin treatment of human BCR/ABL‐positive KCL22 leukemia cells increased IC50 values of imatinib, that is, the drug resistance, in a dose‐dependent manner without any change in the BCR/ABL kinase activity. Imatinib‐induced apoptosis was also suppressed by hemin treatment in KCL22 cells. Hemin treatment increased the activity of γ‐glutamylcysteine synthetase (γ‐GCS) light subunit gene promoter, which contains a Maf recognition element (MARE). Protein levels of γ‐GCS and heme oxygenase‐1 (HO‐1), two MARE‐containing genes, were also increased after hemin treatment. Knockdown of Nrf2 expression by RNA interference largely abolished the effect of hemin on imatinib‐treated cells, suggesting that Nrf2 recognition of MARE is essential for the hemin‐mediated protective effect. Similar to hemin, treatment of cells with δ‐aminolevulinic acid (δ‐ALA), the obligatory heme precursor, also increased IC50 values of imatinib. In contrast, inhibition of cellular heme synthesis by succinylacetone increased the sensitivity of cells to imatinib in two imatinib‐resistant cell lines, KCL22/SR and KU812/SR. Hemin treatment also decreased the sensitivity of cells to four anthracyclins, daunorubicin, idarubicin, doxorubicin, and mitoxantrone, in BCR/ABL‐negative leukemia U937 and THP‐1 cells, as well as in KCL22 cells. These findings thus indicate that cellular heme level plays an important role in determining the sensitivity of cells to imatinib and certain other anti‐leukemia drugs and that the effect of heme may be mediated via its ability to upregulate Nrf2 activity. J. Cell. Biochem. 104: 680–691, 2008. © 2008 Wiley‐Liss, Inc.