Department of Cell Biology and Biophysics, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece.
School of Mechanical Engineering, National Technical University of Athens, Athens, Greece.
J Cell Mol Med. 2019 Dec;23(12):8010-8018. doi: 10.1111/jcmm.14653. Epub 2019 Sep 30.
Multiple myeloma (MM) is a haematological malignancy being characterized by clonal plasma cell proliferation in the bone marrow. Targeting the proteasome with specific inhibitors (PIs) has been proven a promising therapeutic strategy and PIs have been approved for the treatment of MM and mantle-cell lymphoma; yet, while outcome has improved, most patients inevitably relapse. As relapse refers to MM cells that survive therapy, we sought to identify the molecular responses induced in MM cells after non-lethal proteasome inhibition. By using bortezomib (BTZ), epoxomicin (EPOX; a carfilzomib-like PI) and three PIs, namely Rub999, PR671A and Rub1024 that target each of the three proteasome peptidases, we found that only BTZ and EPOX are toxic in MM cells at low concentrations. Phosphoproteomic profiling after treatment of MM cells with non-lethal (IC ) doses of the PIs revealed inhibitor- and cell type-specific readouts, being marked by the activation of tumorigenic STAT3 and STAT6. Consistently, cytokine/chemokine profiling revealed the increased secretion of immunosuppressive pro-tumorigenic cytokines (IL6 and IL8), along with the inhibition of potent T cell chemoattractant chemokines (CXCL10). These findings indicate that MM cells that survive treatment with therapeutic PIs shape a pro-tumorigenic immunosuppressive cellular and secretory bone marrow microenvironment that enables malignancy to relapse.
多发性骨髓瘤（MM）是一种血液系统恶性肿瘤，其特征是骨髓中克隆性浆细胞增殖。用特异性蛋白酶体抑制剂（PIs）靶向蛋白酶体已被证明是一种很有前途的治疗策略，PIs 已被批准用于治疗 MM 和套细胞淋巴瘤；然而，尽管疗效有所改善，但大多数患者最终仍会复发。由于复发是指在治疗后存活下来的 MM 细胞，我们试图确定在 MM 细胞受到非致死性蛋白酶体抑制后诱导的分子反应。通过使用硼替佐米（BTZ）、环氧酶抑制剂（EPOX；一种卡非佐米样 PI）和三种 PI，即 Rub999、PR671A 和 Rub1024，它们分别靶向三种蛋白酶体肽酶，我们发现只有 BTZ 和 EPOX 在低浓度下对 MM 细胞有毒。用非致死性（IC ）剂量的 PI 处理 MM 细胞后进行磷酸蛋白质组学分析，揭示了抑制剂和细胞类型特异性的结果，其特征是致癌 STAT3 和 STAT6 的激活。一致地，细胞因子/趋化因子分析显示，免疫抑制性促肿瘤细胞因子（IL6 和 IL8）的分泌增加，同时强效 T 细胞趋化因子趋化因子（CXCL10）的分泌受到抑制。这些发现表明，用治疗性 PI 治疗后存活下来的 MM 细胞形成了一个促肿瘤发生的免疫抑制性骨髓细胞和分泌微环境，使恶性肿瘤得以复发。
