ABSTRACT
The microenvironment provides a functional substratum supporting tumour growth. Hyaluronan (HA) is a major component of this structure. While the role of HA in malignancy is well-defined, the mechanisms driving its biosynthesis in cancer are poorly understood. We show that the eukaryotic translation initiation factor eIF4E, an oncoprotein, drives HA biosynthesis. eIF4E stimulates production of enzymes that synthesize the building blocks of HA, UDP-Glucuronic acid and UDP-N-Acetyl-Glucosamine, as well as hyaluronic acid synthase which forms the disaccharide chain. Strikingly, eIF4E inhibition alone repressed HA levels as effectively as directly targeting HA with hyaluronidase. Unusually, HA was retained on the surface of high-eIF4E cells, rather than being extruded into the extracellular space. Surface-associated HA was required for eIF4E's oncogenic activities suggesting that eIF4E potentiates an oncogenic HA program. These studies provide unique insights into the mechanisms driving HA production and demonstrate that an oncoprotein can co-opt HA biosynthesis to drive malignancy.
Subject(s)
Eukaryotic Initiation Factor-4E/metabolism , Hyaluronic Acid/biosynthesis , Protein Biosynthesis , Biosynthetic Pathways/genetics , Cell Line , HumansABSTRACT
Chemoresistance remains a major impediment in cancer therapy. Although major progress has been made in understanding the mechanisms underlying resistance in cancer, there is still more to learn. Our studies provide evidence that Gli1 drives a novel form of drug resistance involving Phase II drug metabolism enzymes, specifically the UGT1A family.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Drug Resistance, Neoplasm , Glucuronosyltransferase/metabolism , Protein Processing, Post-Translational , Antineoplastic Agents/therapeutic use , Glioma/drug therapy , Glioma/genetics , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Transcription Factors/genetics , Transcription Factors/metabolism , Zinc Finger Protein GLI1ABSTRACT
Identifying and targeting specific oncogenes, with the hope that the resultant therapies may eventually prove to exert positive clinical effects, is a major effort in the area of cancer therapeutics. The eukaryotic translation initiation factor, eIF4E, is overexpressed in many cancers, including acute myeloid leukemia. The role of eIF4E in oncogenic transformation and the development of a means to directly target its activity with ribavirin are discussed here. Results from early stage clinical trials and factors contributing to the development of clinical resistance to ribavirin are also described.
