Preclinical comparison of proteasome and ubiquitin E1 enzyme inhibitors in cutaneous squamous cell carcinoma: the identification of mechanisms of differential sensitivity
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Angela McHugh1, Kenneth Fernandes1, Andrew P. South2, Jemima E. Mellerio3, Julio C. Salas-Alanís4,5, Charlotte M. Proby1, Irene M. Leigh1,6 and Mark K. Saville1
1Division of Cancer Research, School of Medicine, University of Dundee, Dundee DD1 9SY, UK
2Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA
3St. John’s Institute of Dermatology, King's College London, Guy's Campus, London, SE1 7EH, UK
4DEBRA Mexico, Azteca Guadalupe, Nuevo Leon, 67150 Mexico
5Hospital Regional “Lic. Adolfo Lopez Mateos”, Colonia Florida, Del Alvaro Obregon, 01030 Ciudad de Mexico
6Centre for Cutaneous Research, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK
Mark K. Saville, email: [email protected]
Keywords: squamous cell carcinoma; proteasome; MLN7243/TAK-243; UBA1; UBA6
Received: September 29, 2017 Accepted: March 02, 2018 Published: April 17, 2018
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 bortezomib-resistant 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.
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