Prelowska Monika K, Mehlich Dawid, Ugurlu M Talha, Kedzierska Hanna, Cwiek Aleksandra, Kosnik Artur, Kaminska Klaudia, Marusiak Anna A, Nowis Dominika
Laboratory of Experimental Medicine, Centre of New Technologies, University of Warsaw, Poland; Postgraduate School of Molecular Medicine, Medical University of Warsaw, Poland.
Laboratory of Experimental Medicine, Centre of New Technologies, University of Warsaw, Poland; Doctoral School of Medical University of Warsaw, Warsaw, Poland; Laboratory of Centre for Preclinical Research, Department of Methodology, Medical University of Warsaw, Warsaw, Poland; Laboratory of Experimental Medicine, Medical University of Warsaw, Poland.
Cancer Lett. 2021 Jun 1;507:13-25. doi: 10.1016/j.canlet.2021.02.020. Epub 2021 Mar 10.
Proteasome inhibitors (PIs), used in the treatment of plasma cell myeloma (PCM), interfere with the degradation of misfolded proteins leading to activation of unfolded protein response (UPR) and cell death. However, despite initial strong antimyeloma effects, PCM cells eventually develop acquired resistance to PIs. The pleiotropic role of ʟ-glutamine (Gln) in cellular functions makes inhibition of Gln metabolism a potentially good candidate for combination therapy. Here, we show that PCM cells, both sensitive and resistant to PIs, express membrane Gln transporter (ASCT2), require extracellular Gln for survival, and are sensitive to ASCT2 inhibitors (ASCT2i). ASCT2i synergistically potentiate the cytotoxic activity of PIs by inducing apoptosis and modulating autophagy. Combination of ASCT2 inhibitor V9302 and proteasome inhibitor carfilzomib upregulates the intracellular levels of ROS and oxidative stress markers and triggers catastrophic UPR as shown by upregulated spliced Xbp1 mRNA, ATF3 and CHOP levels. Moreover, analysis of RNA sequencing revealed that the PI in combination with ASCT2i reduced the levels of Gln metabolism regulators such as MYC and NRAS. Analysis of PCM patients' data revealed that upregulated ASCT2 and other Gln metabolism regulators are associated with advanced disease stage and with PIs resistance. Altogether, we identified a potent therapeutic approach that may prevent acquired resistance to PIs and may contribute to the improvement of treatment of patients suffering from PCM.
蛋白酶体抑制剂（PIs）用于治疗浆细胞骨髓瘤（PCM），它会干扰错误折叠蛋白的降解，导致未折叠蛋白反应（UPR）激活和细胞死亡。然而，尽管PIs最初具有强大的抗骨髓瘤作用，但PCM细胞最终会对PIs产生获得性耐药。L-谷氨酰胺（Gln）在细胞功能中具有多效性作用，抑制Gln代谢可能是联合治疗的一个良好候选方案。在此，我们表明，对PIs敏感和耐药的PCM细胞均表达膜Gln转运体（ASCT2），需要细胞外Gln才能存活，并且对ASCT2抑制剂（ASCT2i）敏感。ASCT2i通过诱导细胞凋亡和调节自噬，协同增强PIs的细胞毒活性。ASCT2抑制剂V9302和蛋白酶体抑制剂卡非佐米联合使用可上调细胞内活性氧（ROS）水平和氧化应激标志物，并引发灾难性的UPR，如剪接的Xbp1 mRNA、ATF3和CHOP水平上调所示。此外，RNA测序分析显示，PI与ASCT2i联合使用可降低Gln代谢调节因子如MYC和NRAS的水平。对PCM患者数据的分析表明，ASCT2及其他Gln代谢调节因子上调与疾病晚期和PIs耐药相关。总之，我们确定了一种有效的治疗方法，该方法可能预防对PIs的获得性耐药，并可能有助于改善PCM患者的治疗效果。
