XPO1 is a critical player for bortezomib resistance in multiple myeloma: A quantitative proteomic approach
XPO1 is a critical player for bortezomib resistance in multiple myeloma: A quantitative proteomic approach
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DOI：
10.1016/j.jprot.2019.103504
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发表时间：
2019-10-30
影响因子：
3.3
通讯作者：
Rapole, Srikanth
中科院分区：
文献类型：
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作者：
Chanukuppa, Venkatesh;Paul, Debasish;Rapole, Srikanth
在血癌中，13%的死亡率是由多发性骨髓瘤（MM）型血液恶性肿瘤引起的。尽管化疗治疗取得了进展，但MM仍然是一种无法治愈的疾病，这主要是由于化疗耐药性的出现。目前，硼替佐米是FDA批准的治疗多发性骨髓瘤的一线药物。然而，与其他化疗一样，多发性骨髓瘤患者正在对硼替佐米产生耐药性。本研究旨在使用 iTRAQ 和无标记定量蛋白质组学方法来识别和验证 MM 中的硼替佐米耐药蛋白靶标。两种方法中常见的 112 个差异表达蛋白具有相似的差异表达模式。选择 Exportin-1 (XPO1) 蛋白进行进一步验证，因为在 iTRAQ 和无标记分析中均观察到其显着高表达。对这些常见差异表达蛋白的生物信息分析显示，SMC1A、RCC2、CSE1、NUP88、NUP50、TPR、HSPA14、DYNLL1、RAD21 和 RANBP2 等清晰的蛋白簇与 XPO1 相关。细胞计数测定、流式细胞术测定和软琼脂测定等功能研究证明，RPMI 8226R 细胞系中的 XPO1 敲低会导致对硼替佐米药物的重新敏化。质谱数据可通过 ProteomeXchange 获得，标识符为 PXD013859。 生物学意义：多发性骨髓瘤 (MM) 是一种血液恶性肿瘤，约占所有血细胞相关恶性肿瘤的 13%。化疗耐药是成功治疗MM的主要障碍之一。硼替佐米是第一个蛋白酶体抑制剂药物，广泛用于MM治疗。本研究旨在鉴定和验证 MM 中硼替佐米耐药蛋白靶标。在这里，我们使用全局定量蛋白质组学分析鉴定了 112 个与硼替佐米耐药性相关的候选蛋白质。在这些候选蛋白中，我们通过细胞计数测定、流式细胞术测定和软琼脂测定等功能研究表明，XPO1 在新兴的硼替佐米耐药性中发挥着至关重要的作用。 XPO1 可能是 MM 的潜在治疗靶点，XPO1 抑制剂的开发可能有助于治愈 MM。
Among the blood cancers, 13% mortality is caused by Multiple myeloma (MM) type of hematological malignancy. In spite of therapeutic advances in chemotherapy treatment, still MM remains an incurable disease is mainly due to emergence of chemoresistance. At present time, FDA approved bortezomib is the first line drug for MM treatment. However, like other chemotherapy, MM patients are acquiring resistance against bortezomib. The present study aims to identify and validate bortezomib resistant protein targets in MM using iTRAQ and label free quantitative proteomic approaches. 112 differentially expressed proteins were commonly found in both approaches with similar differential expression pattern. Exportin-1 (XPO1) protein was selected for further validation as its significant high expression was observed in both iTRAQ and label free analysis. Bioinformatic analysis of these common differentially expressed proteins showed a clear cluster of proteins such as SMC1A, RCC2, CSE1, NUP88, NUP50, TPR, HSPA14, DYNLL1, RAD21 and RANBP2 being associated with XPO1. Functional studies like cell count assay, flow cytometry assay and soft agar assay proved that XPO1 knock down in RPMI 8226R cell line results in re-sensitization to bortezomib drug. The mass spectrometry data are available via ProteomeXchange with identifier PXD013859.Biological significance: Multiple myeloma (MM) is a type of hematological malignancy which constitutes about 13% of all blood cell related malignancies. Chemoresistance is one of the major obstacles for the successful treatment for MM. Bortezomib is a first proteasome inhibitor drug, widely used in MM treatment. The present study aims to identify and validate bortezomib resistant protein targets in MM. Here, we identified 112 candidate proteins to be associated with bortezomib resistance using global quantitative proteomic analysis. Among these candidate proteins, we show that XPO1 plays crucial role in emerging bortezomib resistance using functional studies like cell count assay, flow cytometry assay and soft agar assay. XPO1 could be a potential therapeutic target for MM and development of inhibitors of XPO1 might help to cure MM.