Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
Clinical Research Development and Phase I Unit, CREA Laboratory, ASST Spedali Civili di Brescia, Brescia, Italy.
Cancer Res. 2020 Jun 1;80(11):2340-2354. doi: 10.1158/0008-5472.CAN-19-2714. Epub 2020 Feb 24.
Multiple myeloma, the second most common hematologic malignancy, frequently relapses because of chemotherapeutic resistance. Fibroblast growth factors (FGF) act as proangiogenic and mitogenic cytokines in multiple myeloma. Here, we demonstrate that the autocrine FGF/FGFR axis is essential for multiple myeloma cell survival and progression by protecting multiple myeloma cells from oxidative stress-induced apoptosis. In keeping with the hypothesis that the intracellular redox status can be a target for cancer therapy, FGF/FGFR blockade by FGF trapping or tyrosine kinase inhibitor impaired the growth and dissemination of multiple myeloma cells by inducing mitochondrial oxidative stress, DNA damage, and apoptotic cell death that were prevented by the antioxidant vitamin E or mitochondrial catalase overexpression. In addition, mitochondrial oxidative stress occurred as a consequence of proteasomal degradation of the c-Myc oncoprotein that led to glutathione depletion. Accordingly, expression of a proteasome-nondegradable c-Myc protein mutant was sufficient to avoid glutathione depletion and rescue the proapoptotic effects due to FGF blockade. These findings were confirmed on bortezomib-resistant multiple myeloma cells as well as on bone marrow-derived primary multiple myeloma cells from newly diagnosed and relapsed/refractory patients, including plasma cells bearing the t(4;14) translocation obtained from patients with high-risk multiple myeloma. Altogether, these findings dissect the mechanism by which the FGF/FGFR system plays a nonredundant role in multiple myeloma cell survival and disease progression, and indicate that FGF targeting may represent a therapeutic approach for patients with multiple myeloma with poor prognosis and advanced disease stage. SIGNIFICANCE: This study provides new insights into the mechanisms by which FGF antagonists promote multiple myeloma cell death. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/11/2340/F1.large.jpg.
多发性骨髓瘤是第二大常见的血液系统恶性肿瘤，由于化疗耐药而经常复发。成纤维细胞生长因子 (FGF) 在多发性骨髓瘤中作为促血管生成和有丝分裂细胞因子发挥作用。在这里，我们证明了自分泌 FGF/FGFR 轴通过保护多发性骨髓瘤细胞免受氧化应激诱导的细胞凋亡，对于多发性骨髓瘤细胞的存活和进展是必不可少的。与细胞内氧化还原状态可以成为癌症治疗靶点的假说一致，通过 FGF 陷阱或酪氨酸激酶抑制剂阻断 FGF/FGFR，通过诱导线粒体氧化应激、DNA 损伤和凋亡细胞死亡来损害多发性骨髓瘤细胞的生长和扩散，抗氧化维生素 E 或线粒体过氧化氢酶过表达可防止这种情况发生。此外，线粒体氧化应激是由于 c-Myc 癌蛋白的蛋白酶体降解导致谷胱甘肽耗竭而发生的。因此，表达一种不可降解的蛋白酶体 c-Myc 蛋白突变体足以避免谷胱甘肽耗竭，并挽救由于 FGF 阻断而导致的促凋亡作用。这些发现得到了硼替佐米耐药多发性骨髓瘤细胞以及新诊断和复发/难治性患者的骨髓源性原发性多发性骨髓瘤细胞的证实，包括从高风险多发性骨髓瘤患者获得的携带 t(4;14)易位的浆细胞。总而言之，这些发现揭示了 FGF/FGFR 系统在多发性骨髓瘤细胞存活和疾病进展中发挥非冗余作用的机制，并表明针对 FGF 的靶向治疗可能代表一种治疗预后不良和疾病晚期多发性骨髓瘤患者的方法。意义：本研究提供了新的见解，阐明了 FGF 拮抗剂如何促进多发性骨髓瘤细胞死亡。图摘要：http://cancerres.aacrjournals.org/content/canres/80/11/2340/F1.large.jpg。
