Journal
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
Volume 1864, Issue 10, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.bbagen.2020.129650
Keywords
c-MET; Receptor tyrosine kinase; Degradation; Thiosemicarbazones; Cancer therapeutics
Categories
Funding
- National Health and Medical Research Council of Australia (NHMRC) [APP1159596, APP1144829, APP1144456]
- National Breast Cancer Foundation (NBCF) Investigator Initiated Research Scheme Grant [IIRS-19-048]
- Cancer Australia (Priority Driven Collaborative Cancer Research Scheme Grant
- PdCCRS)
- NBCF [APP1146599]
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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.
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