Increased expression of the tight junction protein TJP1/ZO-1 is associated with upregulation of TAZ-TEAD activity and an adult tissue stem cell signature in carfilzomib-resistant multiple myeloma cells and high-risk multiple myeloma patients.
Increased expression of the tight junction protein TJP1/ZO-1 is associated with upregulation of TAZ-TEAD activity and an adult tissue stem cell signature in carfilzomib-resistant multiple myeloma cells and high-risk multiple myeloma patients.
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DOI：
10.18632/oncoscience.356
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发表时间：
2017-07
期刊：
影响因子：
--
通讯作者：
Hawley RG
中科院分区：
文献类型：
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作者：
Riz I;Hawley RG
紧密连接蛋白1(TJP1)最近被认为是识别多发性骨髓瘤(MM)患者最有可能对基于bortezomib和carfizomib的蛋白酶体抑制剂方案有效的生物标志物。在此，我们报告了在适应性反应过程中TJP1表达增加，介导了LP-1/CFZ MM细胞株对卡菲佐米的耐药性。此外，TJP1表达增加描绘了接受基于Bortezomib治疗的复发/难治性MM患者的子集，该患者具有LP-1/CFZ样表型，其特征是河马信号级联(TAZ和TEAD1)相互作用的转录效应器激活和成人组织干细胞特征。SiRNA介导的TJP1或TAZ/TEAD1部分致敏的LP-1/CFZ细胞对卡菲佐米的抑制作用连通性图谱分析确定翻译抑制剂是针对这一分子表型的候选治疗药物。我们证实了这一预测，结果表明，美国食品和药物管理局批准的第一种翻译抑制剂高三尖杉酯碱(甲基丁二酸奥乙酰克辛)对LP-1/CFZ细胞显示出强大的细胞毒活性。高三尖杉酯碱处理降低了TAZ和TEAD1以及MM保护蛋白Nrf2和Mcl1的水平。因此，我们的数据表明了进一步研究翻译抑制剂在复发/难治性MM中的重要性。另一方面，使用TJP1作为蛋白酶体抑制剂敏感性的MM生物标志物需要仔细考虑。
Tight junction protein 1 (TJP1) has recently been proposed as a biomarker to identify multiple myeloma (MM) patients most likely to respond to bortezomib- and carfilzomib-based proteasome inhibitor regimens. Herein we report increased expression of TJP1 during the adaptive response mediating carfilzomib resistance in the LP-1/Cfz MM cell line. Moreover, increased TJP1 expression delineated a subset of relapsed/refractory MM patients on bortezomib-based therapy sharing an LP-1/Cfz-like phenotype characterized by activation of interacting transcriptional effectors of the Hippo signaling cascade (TAZ and TEAD1) and an adult tissue stem cell signature. siRNA-mediated knockdown of TJP1 or TAZ/TEAD1 partially sensitized LP-1/Cfz cells to carfilzomib. Connectivity Map analysis identified translation inhibitors as candidate therapeutic agents targeting this molecular phenotype. We confirmed this prediction by showing that homoharringtonine (omacetaxine mepesuccinate) — the first translation inhibitor to be approved by the U.S. Food and Drug Administration — displayed potent cytotoxic activity on LP-1/Cfz cells. Homoharringtonine treatment reduced the levels of TAZ and TEAD1 as well as the MM-protective proteins Nrf2 and MCL1. Thus, our data suggest the importance of further studies evaluating translation inhibitors in relapsed/refractory MM. On the other hand, use of TJP1 as a MM biomarker for proteasome inhibitor sensitivity requires careful consideration.