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

Angela McHugh, Kenneth Fernandes, Andrew P. South, Jemima E. Mellerio, Julio C. Salas-Alanís, Charlotte M. Proby, Irene M. Leigh, Mark K. Saville

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

© McHugh et al. 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 confers susceptibility to a short incubation with proteasome inhibitors by priming cSCC cells for rapid BAK-dependent death. We observed that bortezomibresistant cSCC cells can be sensitive to MLN7243-induced death. Low expression of the ubiquitin E1 UBA1/UBE1 participates in conferring susceptibility to MLN7243 by increasing sensitivity to MLN7243-mediated attenuation of ubiquitination. This study supports further investigation of the potential of proteasome and ubiquitin E1 inhibition for cSCC therapy. Direct delivery of inhibitors could facilitate adequate exposure of skin cancers.
Original languageEnglish
Pages (from-to)20265-20281
Number of pages17
JournalOncotarget
DOIs
Publication statusPublished - 17 Apr 2018
Externally publishedYes

Fingerprint

Enzyme Inhibitors
Proteasome Endopeptidase Complex
Ubiquitin
Proteasome Inhibitors
Squamous Cell Carcinoma
Skin
Keratinocytes
Cell Line
Ubiquitination
Skin Neoplasms
Therapeutics
Cell- and Tissue-Based Therapy
Cell Survival
Cell Death
Up-Regulation
Pharmacokinetics
Injections
Enzymes

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

McHugh, Angela ; Fernandes, Kenneth ; South, Andrew P. ; Mellerio, Jemima E. ; Salas-Alanís, Julio C. ; Proby, Charlotte M. ; Leigh, Irene M. ; Saville, Mark K. / Preclinical comparison of proteasome and ubiquitin E1 enzyme inhibitors in cutaneous squamous cell carcinoma: The identification of mechanisms of differential sensitivity. In: Oncotarget. 2018 ; pp. 20265-20281.
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Preclinical comparison of proteasome and ubiquitin E1 enzyme inhibitors in cutaneous squamous cell carcinoma: The identification of mechanisms of differential sensitivity. / McHugh, Angela; Fernandes, Kenneth; South, Andrew P.; Mellerio, Jemima E.; Salas-Alanís, Julio C.; Proby, Charlotte M.; Leigh, Irene M.; Saville, Mark K.

In: Oncotarget, 17.04.2018, p. 20265-20281.

Research output: Contribution to journalArticle

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