PIWIL1 Drives Chemoresistance in Multiple Myeloma by Modulating Mitophagy and the Myeloma Stem Cell Population.
PIWIL1 Drives Chemoresistance in Multiple Myeloma by Modulating Mitophagy and the Myeloma Stem Cell Population.
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PIWIL1 通过调节线粒体自噬和骨髓瘤干细胞群来驱动多发性骨髓瘤的化疗耐药性
DOI：
10.3389/fonc.2021.783583
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发表时间：
2021
影响因子：
4.7
通讯作者：
Wu Q
中科院分区：
文献类型：
--
作者：
Wang Y;Yao L;Teng Y;Yin H;Wu Q
PIWI样蛋白1（PIWIL 1）是Argonaute蛋白家族的重要成员，在肿瘤细胞的生存中起着关键作用。然而，PIWIL 1在多发性骨髓瘤（MM）中的确切功能和潜在机制仍不清楚。在这里，我们发现PIWIL 1在骨髓瘤细胞系和新诊断的MM患者中高度表达，并且其表达在难治性/复发性MM患者中明显更高。PIWIL 1促进MM细胞的增殖，并在体外和体内赋予对化疗剂的抗性。更重要的是，PIWIL 1通过破坏线粒体钙信号和调节线粒体吞噬相关的经典PINK 1/Parkin途径蛋白组分来增强自噬体，特别是线粒体吞噬体的形成。线粒体自噬/自噬抑制剂克服PIWIL 1诱导的化学抗性。此外，PIWIL 1过表达增加了侧群（SP）细胞的比例，并上调了干细胞相关基因Nanog、OCT 4和SOX 2的表达，而其抑制则导致相反的效果。综上所述，我们的研究结果表明PIWIL 1通过激活线粒体自噬和调节MM干细胞群体诱导耐药性。PIWIL 1耗竭显著克服了耐药性，可用作逆转MM患者耐药性的新治疗靶点。
As an important member of the Argonaute protein family, PIWI-like protein 1 (PIWIL1) plays a key role in tumor cell viability. However, the exact function of PIWIL1 in multiple myeloma (MM) and the underlying mechanism remain unclear. Here, we revealed that PIWIL1 was highly expressed in myeloma cell lines and newly diagnosed MM patients, and that its expression was notably higher in refractory/relapsed MM patients. PIWIL1 promoted the proliferation of MM cells and conferred resistance to chemotherapeutic agents both in vitro and in vivo. More importantly, PIWIL1 enhanced the formation of autophagosomes, especially mitophagosomes, by disrupting mitochondrial calcium signaling and modulating mitophagy-related canonical PINK1/Parkin pathway protein components. Mitophagy/autophagy inhibitors overcome PIWIL1-induced chemoresistance. In addition, PIWIL1 overexpression increased the proportion of side population (SP) cells and upregulated the expression of the stem cell-associated genes Nanog, OCT4, and SOX2, while its inhibition resulted in opposite effects. Taken together, our findings demonstrated that PIWIL1 induced drug resistance by activating mitophagy and regulating the MM stem cell population. PIWIL1 depletion significantly overcame drug resistance and could be used as a novel therapeutic target for reversing resistance in MM patients.
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影响因子：
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