University of South Carolina School of Medicine Greenville, University of South Carolina, Greenville, SC, United States.
Research and Development Department, Organogenesis, Birmingham, AL, United States.
Front Immunol. 2022 May 19;13:889954. doi: 10.3389/fimmu.2022.889954. eCollection 2022.
The role of the unfolded protein response (UPR) in plasma cells (PC) and their malignant multiple myeloma (MM) counterparts is a well described area of research. The importance of autophagy in these cells, as well as the interplay between autophagy and the UPR system, has also been well studied. In this review, we will discuss the relationship between these two cellular responses and how they can be utilized in MM to account for the high levels of monoclonal immunoglobulin (Ig) protein synthesis that is characteristic of this disease. Interactions between MM cells and the bone marrow (BM) microenvironment and how MM cells utilize the UPR/autophagy pathway for their survival. These interacting pathways form the foundation for the mechanism of action for bortezomib, a proteasome inhibitor used to modify the progression of MM, and the eventual drug resistance that MM cells develop. One important resistance pathway implicated in MM progression is caspase 10 which attenuates autophagy to maintain its prosurvival function and avoid cell death. We lay a groundwork for future research including 3D models for better disease monitoring and personalized treatment. We also highlight pathways involved in MM cell survival and drug resistance that could be used as new targets for effective treatment.
未折叠蛋白反应（UPR）在浆细胞（PC）及其恶性多发性骨髓瘤（MM）对应物中的作用是一个研究得很好的领域。自噬在这些细胞中的重要性，以及自噬和 UPR 系统之间的相互作用，也得到了很好的研究。在这篇综述中，我们将讨论这两种细胞反应之间的关系，以及它们如何在 MM 中被利用，以解释这种疾病特有的高水平单克隆免疫球蛋白（Ig）蛋白合成。MM 细胞与骨髓（BM）微环境的相互作用以及 MM 细胞如何利用 UPR/自噬途径来生存。这些相互作用的途径为硼替佐米（一种用于修饰 MM 进展的蛋白酶体抑制剂）的作用机制以及 MM 细胞最终产生的耐药性奠定了基础。在 MM 进展中涉及的一个重要耐药途径是半胱天冬酶 10，它减弱自噬以维持其促生存功能并避免细胞死亡。我们为未来的研究奠定了基础，包括用于更好地疾病监测和个性化治疗的 3D 模型。我们还强调了涉及 MM 细胞存活和耐药性的途径，这些途径可以作为新的有效治疗靶点。
