Preclinical comparison of proteasome and ubiquitin E1 enzyme inhibitors in cutaneous squamous cell carcinoma: the identification of mechanisms of differential sensitivity

Oncotarget
Angela McHughMark K Saville

Abstract

Proteasome inhibitors have distinct properties and the biochemical consequences of suppressing ubiquitin E1 enzymes and the proteasome differ. We compared the effects of the proteasome inhibitors bortezomib, ixazomib and carfilzomib and the ubiquitin E1 enzyme inhibitor MLN7243/TAK-243 on cell viability and cell death in normal keratinocytes and cutaneous squamous cell carcinoma (cSCC) cell lines. The effects of both a pulse of treatment and more extended incubation were investigated. This is relevant to directly-delivered therapy (topical treatment/intratumoral injection) where the time of exposure can be controlled and a short exposure may better reflect systemically-delivered inhibitor pharmacokinetics. These agents can selectively kill cSCC cells but there are variations in the pattern of cSCC cell line sensitivity/resistance. Variations in the responses to proteasome inhibitors are associated with differences in the specificity of the inhibitors for the three proteolytic activities of the proteasome. There is greater selectivity for killing cSCC cells compared to normal keratinocytes with a pulse of proteasome inhibitor treatment than with a more extended exposure. We provide evidence that c-MYC-dependent NOXA upregulation...Continue Reading

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Citations

Nov 20, 2018·Expert Opinion on Therapeutic Patents·Xin LiQ Ping Dou
Nov 13, 2020·Pharmacological Reviews·Samir H Barghout, Aaron D Schimmer
Feb 26, 2021·Oncogene·Ethan L MorganAndrew Macdonald

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Methods Mentioned

BETA
ubiquitination
transfection
Assay
electrophoresis

Clinical Trials Mentioned

NCT02045095

Software Mentioned

GraphPad
GraphPad Prism

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