N-Terminal-Dependent Protein Degradation and Targeting Cancer Cells.

Intracellular protein degradation is mediated selectively by the Ubiquitin Proteasome System (UPS) and autophagic-lysosomal system in mammalian cells. Many cellular and physiological processes, such as cell division, cell differentiation, and cellular demise. are fine-tuned via the UPS-mediated protein degradation. Notably, impairment of UPS contributes to human disorders including cancer and neurodegeneration. The proteasome-dependent N-degron pathways mediate the degradation of proteins through their destabilizing amino-terminal residues. Recent advances unveiled that targeting N-degron proteolytic pathways can aid in sensitizing some cancer cells to chemotherapeutic agents. Furthermore, interestingly, exploiting the N-degron feature, the simplest degradation signal in mammals, and fusing it to a ligand specific for Estrogen-Related Receptor alpha (ERRa) has demonstrated its utility in ERRa knockdown, via Nterminal dependent degradation, and also its efficiency in the inhibition of growth of breast cancer cells. These recent advances uncover the therapeutic implications of targeting and exploiting N-degron proteolytic pathways to curb growth and migration of cancer cells.