Alteration of mitochondrial biogenesis promotes disease progression in multiple myeloma.
Alteration of mitochondrial biogenesis promotes disease progression in multiple myeloma.
复制标题
DOI：
10.18632/oncotarget.22740
复制
发表时间：
2017-12-19
期刊：
影响因子：
--
通讯作者：
Tricot G
中科院分区：
文献类型：
--
作者：
Zhan X;Yu W;Franqui-Machin R;Bates ML;Nadiminti K;Cao H;Amendt BA;Jethava Y;Frech I;Zhan F;Tricot G
包括多发性骨髓瘤（MM）在内的许多癌症都会保留更多的胞浆铁，以促进肿瘤细胞生长和耐药性。较高的胞质铁促进氧化损伤，这是由于其与线粒体产生的活性氧相互作用。使用大型临床数据集中的基因表达谱评估MM疾病不同阶段中线粒体生物发生的变化。与正常浆细胞相比，18个线粒体生物发生相关基因组中有16个（包括线粒体生物发生特征和氧化磷酸化）在骨髓瘤细胞中增加，高表达与较差的患者结局相关。复发和耐药骨髓瘤样品比新诊断的患者样品具有更高的线粒体生物发生特征表达。线粒体生物发生基因的表达受细胞铁含量的调节，这在MM患者的预后中显示出协同效应。在体内模型中，药理学抗坏血酸通过抑制线粒体氧化磷酸化诱导骨髓瘤细胞死亡。在这里，我们确定，失调的线粒体生物合成和铁稳态发挥了重要作用，骨髓瘤进展和患者的结果和药理抗坏血酸，通过细胞铁含量和线粒体氧化物种，应被视为一种新的治疗骨髓瘤，包括耐药和复发患者。
Many cancers, including multiple myeloma (MM), retain more cytosolic iron to promote tumor cell growth and drug resistance. Higher cytosolic iron promotes oxidative damage due to its interaction with reactive oxygen species generated by mitochondria. The variation of mitochondrial biogenesis in different stages of MM disease was evaluated using gene expression profiles in a large clinical dataset. Sixteen of 18mitochondrial biogenesis related gene sets, including mitochondrial biogenesis signature and oxidative phosphorylation, were increased in myeloma cells compared with normal plasma cells and high expression was associated with an inferior patient outcome. Relapsed and drug resistant myeloma samples had higher expression of mitochondrial biogenesis signatures than newly diagnosed patient samples. The expression of mitochondrial biogenesis genes was regulated by the cellular iron content, which showed a synergistic effect in patient outcome in MM. Pharmacological ascorbic acid induced myeloma cell death by inhibition of mitochondria oxidative phosphorylation in an in vivo model. Here, we identify that dysregulated mitochondrial biogenesis and iron homeostasis play a major role in myeloma progression and patient outcome and that pharmacological ascorbic acid, through cellular iron content and mitochondrial oxidative species, should be considered as a novel treatment in myeloma including drug-resistant and relapsed patients.
登录
查看更多内容
影响因子：
64.5
作者：
Vyas S;Zaganjor E;Haigis MC
通讯作者：
Haigis MC
影响因子：
64.5
作者：
Pospisilik, J. Andrew;Knauf, Claude;Penninger, Josef M.
通讯作者：
Penninger, Josef M.
影响因子：
11.4
作者：
Vahsen, N;Candé, C;Kroemer, G
通讯作者：
Kroemer, G
AIF 和 CHCHD4 之间的相互作用调节呼吸链生物发生。
影响因子：
16
作者：
Hangen, Emilie;Feraud, Olivier;Modjtahedi, Nazanine
通讯作者：
Modjtahedi, Nazanine
影响因子：
28.5
作者：
Gu Z;Xia J;Xu H;Frech I;Tricot G;Zhan F
通讯作者：
Zhan F