Targeting Protein Degradation Pathways in Tumors: Focusing on their Role in Hematological Malignancies

Abstract

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.

Targeted Strategies for Degradation of Key Transmembrane Proteins in Cancer

“…In short, it removes the poly-Ub, unfolds the protein, and moves it into the inner chamber of the complexing protein. The synthesis of the 26S proteasome requires a significant amount of energy, and there are various mechanisms that regulate the adequate production of proteasome elements [ 78 ].…”

Gold Nanoparticle-Mediated Gene Therapy

“…In addition, hybridized AuNPs could kill L. major in addition to silencing the GP63 gene. A detailed review was published on protein degradation pathways in hematological malignancies, in which the specific number of stress categories which lead to protein degradation and unsuccessful treatment was studied [ 126 ]. Additionally, AuNPs could potentially aid in the study of genetic diseases.…”

H2O2mediated MAPK-mTOR crosstalk determines the XIAP and FLIP degradation pathways and development of resistance to Imatinib

“…Therefore, inhibition of the proteasome is an area of interest in cancer research. In a variety of cancers proteasome inhibition has been shown to persuade apoptosis [3,4].…”