Targeting Proteasomes in Cancer and Infectious Disease: A Parallel Strategy to Treat Malignancies and Microbes

Abstract

Essential core pathways of cellular biology are preserved throughout evolution, highlighting the importance of these pathways for both bacteria and human cancer cells alike. Cell viability requires a proper balance between protein synthesis and degradation in order to maintain integrity of the proteome. Proteasomes are highly intricate, tightly regulated multisubunit complexes that are critical to achieve protein homeostasis (proteostasis) through the selective degradation of misfolded, redundant and damaged proteins. Proteasomes function as the catalytic core of the ubiquitin-proteasome pathway (UPP) which regulates a myriad of essential processes including growth, survival, differentiation, drug resistance and apoptosis. Proteasomes recognize and degrade proteins that have been marked by covalently attached poly-ubiquitin chains. Deregulation of the UPP has emerged as an essential etiology of many prominent diseases, including cancer. Proteasome inhibitors selectively target cancer cells, including those resistant to chemotherapy, while sparing healthy cells. Proteasome inhibition has emerged as a transformative anti-myeloma strategy that has extended survival for certain patient populations from 3 to 8 years. The structural architecture and functional activity of proteasomes is conserved from Archaea to humans to support the concept that proteasomes are actionable targets that can be inhibited in pathogenic organisms to improve the treatment of infectious diseases. Proteasomes have an essential role during all stages of the parasite life cycle and features that distinguish proteasomes in pathogens from human forms have been revealed. Advancement of inhibitors that target Plasmodium and Mycobacterial proteasomes is a means to improve treatment of malaria and tuberculosis. In addition, PIs may also synergize with current frontline agents support as resistance to conventional drugs continues to increase. The proteasome represents a highly promising, actionable target to combat infectious diseases that devastate lives and livelihoods around the globe.

Shutting off the fuel supply to target metabolic vulnerabilities in multiple myeloma

“…Multiple myeloma (MM) is a cancer of terminally-differentiated plasma cells (PCs) that accumulate and proliferate predominantly within the tumor permissive BM microenvironment ( 20 – 25 ). PCs are primary effectors of humoral immunity and function as antibody-producing factories that secrete vast amount of immunoglobulins.…”

Targeting Proteasomes and the MHC Class I Antigen Presentation Machinery to Treat Cancer, Infections and Age-Related Diseases

“…Worldwide, cancer and infectious disease are major causes of morbidity and mortality, and while the causative agents and molecular mechanisms of disease may differ, they share many pathophysiologic similarities [19,[102][103][104]. Proteasomes are conserved throughout evolution and contribute to the cell biology and viability of parasites, and unicellular and multicellular organisms [105][106][107].…”

“…The 26S proteasome is a ~2.5 MDa, ATP-hydrolyzing proteolytic machine that functions as the protein-hydrolyzing catalytic core component of the UPS [16][17][18][19]. 26S proteasomes are assembled in an ATP-dependent reaction and are comprised of two subcomplexes, namely a 20S core particle (CP) and 19S regulatory particles (RPs, PA700) that cap either or both ends of the 20S CP [20,21].…”

Targeting TGF-β signaling in the multiple myeloma microenvironment: Steering CARs and T cells in the right direction

“…Moreover, the proteasome inhibitors bortezomib and carfilzomib have shown significant promise in targeting plasma cells that secrete HLA-antibodies and hinder organ transplantation ( Tremblay et al, 2020 ; Woodle et al, 2020 ). TGF-β/Smad signaling has been shown to regulate expression of the proteasome catalytic subunit PSMB5 ( Lai et al, 2018 ) and a number of studies suggest that PSMB5 contributes to proteasome inhibitor resistance ( Oerlemans et al, 2008 ; Ignatz-Hoover et al, 2022 ). Studies in bortezomib-resistant myelomonocytic cells revealed PSMB5 overexpression, mutations within the highly conserved bortezomib binding pocket in PSMB5 and that PSMB5 knockdown restored drug sensitivity.…”