Research Progress of New Targets and Strategies to Regulate Proteostasis in Cancer

Proteostasis deregulation, which is closely related to malignant tumors and other major diseases, is caused by such factors as altered protein synthesis, abnormal protein folding and post-translational modifications, as well as the deregulation of protein degradation pathways like the ubiquitin-proteasome system or the autophagy-lysosomal system. In recent years, plenty of studies have shown that proteostasis deregulation may result in endoplasmic reticulum stress and abnormal function of important organelles such as mitochondria, thus leading to abnormal accumulation of oncoprotein or excessive degradation of tumor suppressor protein and further promoting tumorigenesis. Since proteostasis is extensively involved in various stages of tumor malignancy, intervention strategies based on the key molecular mechanisms or crucial functional proteins of proteostasis regulation are important areas in anti-tumor drug research and development. Drugs targeting proteasomes and E3 ubiquitin ligases have been clinically utilized for the treatment of multiple myeloma, and a series of protein degradation technologies such as proteolysis-targeting chimera (PROTAC) and lysosome-targeting chimera (LYTAC) have emerged as promising strategies. This article reviews the research progress in the areas of proteostasis regulation, and summarizes the (candidate) drugs, targets and indications that have been approved or are under clinical research, in an attempt to provide some insight and reference for an in-depth understanding of proteostasis regulation mechanisms and further expansion of their application in cancer treatment.