Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
Cancer Med. 2023 Apr;12(8):9709-9722. doi: 10.1002/cam4.5679. Epub 2023 Feb 12.
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% O ). 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.
多发性骨髓瘤（MM）是一种血液恶性肿瘤，近年来已可获得蛋白酶体抑制剂进行治疗。然而，许多患者在治疗过程中对这些药物产生了耐药性。因此，阐明蛋白酶体抑制剂耐药性获得的机制非常重要。侧群（SP）细胞具有高药物外排能力和缺氧微环境中的低氧反应，这两者都为 MM 中的耐药性提供了重要的见解；然而，关于缺氧微环境中 SP 细胞的特征知之甚少。
我们对 RPMI-8226 和 KMS-11 细胞系的 SP 和非 SP 细胞进行了 cDNA 微阵列分析，这些细胞在常氧和缺氧条件（1% O ）下培养 48 小时。检查了在缺氧 SP 中特异性上调的基因。
我们全面的基因表达分析确定了 HMOX1、BACH2 和 DUX4 作为在缺氧条件下 SP 细胞中特异性高表达的蛋白质编码基因。我们已经表明，HMOX1/血红素加氧酶-1（HMOX1/HO-1）由缺氧诱导的活性氧（ROS）诱导，并降低 ROS 水平。此外，我们发现 HMOX1 有助于体外和体内缺氧诱导的蛋白酶体抑制剂耐药性。过多的 ROS 水平协同增强硼替佐米的敏感性。在临床数据集中，HMOX1 与 MAFB 具有很强且显著的正相关，但与 MAF 无关。有趣的是，缺氧刺激增加了骨髓瘤细胞中 MAFB/MafB 的表达；此外，在缺氧条件下敲低 MAFB 可抑制 HMOX1 的表达。
这些结果表明，缺氧-ROS-HMOX1 轴和缺氧诱导的 MafB 可能是缺氧微环境中蛋白酶体抑制剂耐药性的重要机制。
