Targeting mammalian N-end rule pathway for cancer therapy

Abstract

Regulated protein degradation plays a crucial role in maintaining proteostasis along with protein refolding and compartmentalisation which collectively control biological functions. The N-end rule pathway is a major ubiquitin-dependent protein degradation system. The short-lived protein substrates containing destabilizing amino acid residues (N-degrons) are recognized by E3 ubiquitin ligases containing UBR box domains (N-recognin) for degradation. The dysregulated pathway fails to maintain the metabolic stability of the substrate proteins which leads to diseases. The mammalian substrates of this pathway are involved in many hallmarks of cancer such as resisting cell death, evading growth suppression, chromosomal instability, angiogenesis, and deregulation of cellular metabolism. Besides, mutations in E3 N-recognin have been detected in human cancers. In this review, we discuss the mammalian N-end rule pathway components, functions, and mechanism of degradation of substrates, and their implications in cancer pathogenesis. We also discuss the impact of pharmacological and genetic inhibition of this pathway component on cancer cells and chemoresistance. We further highlight how this pathway can be manipulated for selective protein degradation; for instance, using PROTAC technique. The challenges and future perspectives to utilize this pathway as a drug target for cancer therapy are also discussed.

Keywords: Cancer; N-degron; N-recognin; Program cell death; Small molecule inhibitors; Therapeutics.