Hypoxia-induced oxidative stress promotes therapy resistance via upregulation of heme oxygenase-1 in multiple myeloma.
Hypoxia-induced oxidative stress promotes therapy resistance via upregulation of heme oxygenase-1 in multiple myeloma.
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DOI：
10.1002/cam4.5679
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发表时间：
2023-04
期刊：
影响因子：
4
通讯作者：
Takahashi, Naoto
中科院分区：
文献类型：
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作者：
Abe, Ko;Ikeda, Sho;Nara, Miho;Kitadate, Akihiro;Tagawa, Hiroyuki;Takahashi, Naoto
多发性骨髓瘤（MM）是一种造血恶性肿瘤，蛋白酶体抑制剂近年来已成为可用。然而，许多患者在治疗期间对这些药物产生耐药性。因此，阐明蛋白酶体抑制剂获得耐药性的机制是很重要的。侧群（SP）细胞在微环境中具有较高的药物外排能力和缺氧反应，为MM耐药提供了重要的见解；然而，对SP细胞在缺氧微环境下的特性了解甚少。我们对RPMI‐8226和KMS‐11细胞系在常氧和低氧条件下（1% O2）培养48小时获得的SP和非SP进行了cDNA芯片分析。研究了在缺氧SP中特异性上调的基因。我们的综合基因表达分析发现HMOX1、BACH2和DUX4是在缺氧条件下SP细胞中特异性高表达的蛋白编码基因。我们已经证明HMOX1/血红素加氧酶‐1 （HMOX1/HO‐1）是由缺氧诱导的活性氧（ROS）诱导的，并降低ROS水平。此外，我们发现HMOX1在体外和体内都有助于缺氧诱导对蛋白酶体抑制剂的抗性。过量的活性氧水平协同增强硼替佐米敏感性。在临床数据集中，HMOX1与MAFB呈显著正相关，而与MAF无显著正相关。有趣的是，缺氧刺激增加了骨髓瘤细胞中MAFB/ MAFB的表达；此外，缺氧条件下MAFB的下调抑制了HMOX1的表达。这些结果表明，缺氧- ROS - HMOX1轴和缺氧诱导的mab可能是缺氧微环境中蛋白酶体抑制剂耐药的重要机制。通过详细检查暴露于缺氧的侧群（SP）细胞中高表达基因的功能，我们阐明了缺氧- ROS - HMOX1轴在缺氧环境中对蛋白酶体抑制剂抗性的贡献。这条轴也可能参与缺氧诱导的MafB表达。
Multiple myeloma (MM) is a hematopoietic malignancy for which proteasome inhibitors have become available in recent years. However, many patients develop resistance to these drugs during treatment. Therefore, it is important to elucidate the mechanisms underlying resistance acquisition by proteasome inhibitors. Side population (SP) cells, which have a high drug efflux capacity and hypoxic responses in the microenvironment have both provided important insights into drug resistance in MM; however, little is known about the characteristics of SP cells in hypoxic microenvironments. We performed cDNA microarray analysis for SP and non‐SP obtained from RPMI‐8226 and KMS‐11 cell lines cultured for 48 h in normoxic and hypoxic conditions (1% O2). Genes specifically upregulated in hypoxic SP were examined. Our comprehensive gene expression analysis identified HMOX1, BACH2, and DUX4 as protein‐coding genes that are specifically highly expressed in SP cells under hypoxic conditions. We have shown that HMOX1/heme oxygenase‐1 (HMOX1/HO‐1) is induced by hypoxia‐inducible reactive oxygen species (ROS) and reduces ROS levels. Furthermore, we found that HMOX1 contributes to hypoxia‐induced resistance to proteasome inhibitors in vitro and in vivo. Excessive ROS levels synergistically enhance bortezomib sensitivity. In clinical datasets, HMOX1 had a strong and significantly positive correlation with MAFB but not MAF. Interestingly, hypoxic stimulation increased MAFB/MafB expression in myeloma cells; in addition, the knockdown of MAFB under hypoxic conditions suppressed HMOX1 expression. These results suggest that the hypoxia‐ROS‐HMOX1 axis and hypoxia‐induced MafB may be important mechanisms of proteasome inhibitor resistance in hypoxic microenvironments. By examining in detail the function of genes that are highly expressed in side population (SP) cells exposed to hypoxia, we clarified the contribution of the hypoxia‐ROS‐HMOX1 axis to proteasome inhibitor resistance in hypoxic environments. This axis might also be involved in hypoxia‐induced MafB expression.
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影响因子：
56.9
作者：
Jaakkola, P;Mole, DR;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
DOI：
10.1111/j.1349-7006.2001.tb01142.x
发表时间：
2001-06
期刊：
Japanese journal of cancer research : Gann
影响因子：
--
作者：
Hanamura I;Iida S;Akano Y;Hayami Y;Kato M;Miura K;Harada S;Banno S;Wakita A;Kiyoi H;Naoe T;Shimizu S;Sonta SI;Nitta M;Taniwaki M;Ueda R
通讯作者：
Ueda R
影响因子：
3.7
作者：
Boesch, Maximilian;Reimer, Daniel;Wolf, Dominik
通讯作者：
Wolf, Dominik
影响因子：
4.8
作者：
Lee, PJ;Jiang, BH;Choi, AMK
通讯作者：
Choi, AMK
缺氧诱导的氧化应激会通过自噬促进MUC4降解，从而增强胰腺癌细胞的存活。
影响因子：
8
作者：
通讯作者：
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