PHLPP Sensitizes Multiple Myeloma Cells to Bortezomib Through Regulating LAMP2
PHLPP Sensitizes Multiple Myeloma Cells to Bortezomib Through Regulating LAMP2
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PHLPP 通过调节 LAMP2 使多发性骨髓瘤细胞对硼替佐米敏感
DOI：
10.2147/ott.s237343
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发表时间：
2020-01-01
影响因子：
4
通讯作者：
Liu, Jing
中科院分区：
文献类型：
--
作者：
Liu, Xiao;Li, Chengyuan;Liu, Jing
波特佐米(BTZ)的引进治疗改善了多发性骨髓瘤(MM)患者的临床结果。然而，BTZ的原发耐药和获得性耐药常发生在MM患者中。PH域富含亮氨酸重复蛋白磷酸酶(PHLPP)在许多癌症的化疗耐药中起重要作用。然而，PHLPP在多发性骨髓瘤中的作用尚不清楚。在这项研究中，我们研究了PHLPP在BTZ耐药MM细胞中的作用。方法采用BrdU比色法、免疫沉淀法、流式细胞术和免疫荧光法。结果与BTZ敏感的MM细胞相比，BTZ耐药的MM细胞PHLPP和溶酶体膜蛋白2(LAMP2)水平下调，并伴有自噬途径失活，表现为Beclin1、ATG5和LC3B的表达减少，p62的表达增加。获得和丧失功能的实验表明，PHLPP部分地使MM细胞对BTZ重新敏感。此外，PHLPP过表达增加，而PHLPP基因敲除降低了LAMP2的表达，从而调节了MM细胞的自噬途径。进一步的研究结果表明，LAMP2基因敲除逆转了PHLPP介导的MM细胞的细胞凋亡和自噬激活。结论PHLPP是克服MM患者BTZ耐药的一种潜在策略。
Introduction Treatment of bortezomib (BTZ) improves the clinical outcomes of patients with multiple myeloma (MM). However, primary resistance and acquired resistance to BTZ frequently develop in patients with MM. PH domain leucine-rich repeat protein phosphatase (PHLPP) plays an important role in chemoresistance in a number of cancers. However, the role of PHLPP on MM remains unclear. In this study, we investigated the role of PHLPP in BTZ-resistant MM cells. Methods BrdU assays, immunoprecipitation, flow cytometry analyses, and immunofluorescence assays were performed. Results PHLPP and lysosome-associated membrane protein 2 (LAMP2) levels were downregulated in BTZ-resistant MM cells compared with BTZ-sensitive MM cells, accompanied by inactivation of autophagy pathway evaluated by a reduction in Beclin1, Atg5 and LC3B and increase in p62. Gain- and loss-of-function experiments revealed that PHLPP partially re-sensitized MM cells to BTZ. In addition, PHLPP overexpression increased whereas PHLPP knockdown reduced LAMP2 expression, subsequently regulating the autophagy pathway in MM cells. Further findings demonstrated that LAMP2 knockdown reversed PHLPP-mediated cell apoptosis and autophagy activation in MM cells. Conclusion This study demonstrated that PHLPP is a potential strategy for overcoming BTZ resistance in patients with MM.