Wang Yajun, Yao Lan, Teng Yao, Yin Hua, Wu Qiuling
Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Front Oncol. 2022 Jan 10;11:783583. doi: 10.3389/fonc.2021.783583. eCollection 2021.
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 and . 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 , , and , 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.
作为Argonaute蛋白家族的重要成员，PIWI样蛋白1（PIWIL1）在肿瘤细胞生存能力中起关键作用。然而，PIWIL1在多发性骨髓瘤（MM）中的具体功能及潜在机制仍不清楚。在此，我们发现PIWIL1在骨髓瘤细胞系和新诊断的MM患者中高表达，且在难治性/复发性MM患者中其表达显著更高。PIWIL1促进MM细胞增殖并赋予对化疗药物的抗性。更重要的是，PIWIL1通过破坏线粒体钙信号和调节与线粒体自噬相关的经典PINK1/帕金通路蛋白成分，增强自噬体尤其是线粒体自噬体的形成。线粒体自噬/自噬抑制剂可克服PIWIL1诱导的化疗抗性。此外，PIWIL1过表达增加了侧群（SP）细胞比例并上调了干细胞相关基因、和的表达，而对其抑制则产生相反效果。综上所述，我们的研究结果表明PIWIL1通过激活线粒体自噬和调节MM干细胞群体诱导耐药性。PIWIL1缺失显著克服耐药性，可作为逆转MM患者耐药性的新型治疗靶点。
