Cellular Responses to Proteasome Inhibition: Molecular Mechanisms and Beyond

Area of Science:

• Biochemistry
• Cell Biology
• Pharmacology

Background:

• Proteasome inhibitors are investigated for cancer, inflammatory, and autoimmune diseases.
• Cellular adaptive responses limit proteasome inhibitor efficacy and cause side effects.
• Understanding these adaptations is key to improving therapeutic outcomes.

Purpose of the Study:

• To review proteasome complexes, regulators, and adaptive cellular responses to proteasome inhibition.
• To discuss the role of the Autophagic-Lysosomal Pathway (ALP), proteaphagy, and transcription factors Nrf1/Nrf2.
• To explore the involvement of IRE1, PERK, Rpn11, and USP14 in these adaptive processes.

Main Methods:

• Literature review and synthesis of existing research on proteasome inhibition.
• Analysis of cellular adaptive mechanisms, including autophagy and proteasome biogenesis.
• Discussion of specific molecular players like transcription factors and deubiquitinases.

Main Results:

• Cells activate adaptive responses, including the Autophagic-Lysosomal Pathway (ALP), to survive proteasome inhibition.
• Proteaphagy, p62/SQSTM1 bodies, and Nrf1/Nrf2-dependent proteasome biogenesis are key adaptive mechanisms.
• IRE1, PERK, Rpn11, and USP14 play significant roles in ALP activation and cellular response.

Conclusions:

• Cellular adaptation mechanisms, particularly ALP activation, hinder the effectiveness of current proteasome inhibitors.
• Further research into these adaptive pathways is essential for developing novel therapeutic strategies.
• Targeting proteasome activity requires consideration of these complex cellular responses to overcome resistance and minimize side effects.