The c-MET oncoprotein: Function, mechanisms of degradation and its targeting by novel anti-cancer agents

Abstract

Background: The c-MET oncoprotein drives cancer progression in a variety of tumors through its signaling transduction pathways. This oncoprotein is also degraded by multiple mechanisms involving the lysosome, proteasome and cleavage by proteases. Targeting c-MET degradation pathways may result in effective therapeutic strategies.

Scope of review: Since the discovery of oncogenic functions of c-MET, there has been a great deal of effort to develop anti-cancer drugs targeting this oncoprotein. Unexpectedly, novel di-2-pyridylketone thiosemicarbazones that demonstrate marked anti-tumor activity, down-regulate c-MET through their ability to bind intracellular iron and via mechanisms including, down-regulation of MET mRNA, enhanced lysosomal processing and increased metalloprotease-mediated cleavage.

Major conclusions: The c-MET oncoprotein regulation and degradation pathways are complex. However, with increasing understanding of its degradation mechanisms, there is also greater opportunities to therapeutically target these pathways.

General significance: Understanding the mechanisms of degradation of c-MET protein and its regulation could lead to novel therapeutics.

Keywords: Cancer therapeutics; Degradation; Receptor tyrosine kinase; Thiosemicarbazones; c-MET.