Wolska-Washer Anna, Smolewski Piotr
Department of Experimental Hematology, Medical University of Lodz, 93-510 Lodz, Poland.
Cancers (Basel). 2022 Aug 3;14(15):3778. doi: 10.3390/cancers14153778.
Cells must maintain their proteome homeostasis by balancing protein synthesis and degradation. This is facilitated by evolutionarily-conserved processes, including the unfolded protein response and the proteasome-based system of protein clearance, autophagy, and chaperone-mediated autophagy. In some hematological malignancies, including acute myeloid leukemia, misfolding or aggregation of the wild-type p53 tumor-suppressor renders cells unable to undergo apoptosis, even with an intact p53 DNA sequence. Moreover, blocking the proteasome pathway triggers lymphoma cell apoptosis. Extensive studies have led to the development of proteasome inhibitors, which have advanced into drugs (such as bortezomib) used in the treatment of certain hematological tumors, including multiple myeloma. New therapeutic options have been studied making use of the so-called proteolysis-targeting chimeras (PROTACs), that bind desired proteins with a linker that connects them to an E3 ubiquitin ligase, resulting in proteasomal-targeted degradation. This review examines the mechanisms of protein degradation in the cells of the hematopoietic system, explains the role of dysfunctional protein degradation in the pathogenesis of hematological malignancies, and discusses the current and future advances of therapies targeting these pathways, based on an extensive search of the articles and conference proceedings from 2005 to April 2022.
细胞必须通过平衡蛋白质合成和降解来维持其蛋白质组稳态。这通过进化上保守的过程来实现，包括未折叠蛋白反应、基于蛋白酶体的蛋白质清除系统、自噬和伴侣介导的自噬。在一些血液系统恶性肿瘤中，包括急性髓系白血病，野生型p53肿瘤抑制因子的错误折叠或聚集使细胞即使在p53 DNA序列完整的情况下也无法发生凋亡。此外，阻断蛋白酶体途径会触发淋巴瘤细胞凋亡。广泛的研究导致了蛋白酶体抑制剂的开发，这些抑制剂已发展成为用于治疗某些血液系统肿瘤（如多发性骨髓瘤）的药物（如硼替佐米）。利用所谓的蛋白酶靶向嵌合体（PROTAC）研究了新的治疗选择，PROTAC通过连接子将所需蛋白质与E3泛素连接酶连接，从而导致蛋白酶体靶向降解。本综述基于对2005年至2022年4月的文章和会议记录的广泛搜索，研究了造血系统细胞中蛋白质降解的机制，解释了功能失调的蛋白质降解在血液系统恶性肿瘤发病机制中的作用，并讨论了针对这些途径的治疗方法的当前和未来进展。
