Targeting the ubiquitin-proteasome system for cutaneous SCC therapy

We have an interest in the targeting the ubiquitin-proteasome system for cancer therapy [1-4]. Regulation of the stability, activity and localization of proteins through ubiquitination is critical in the control of many fundamental processes of relevance to cancer and its therapy including: DNA repair, cell cycle progression and apoptosis.  Furthermore, proteins involved in the ubiquitin system are dysregulated in cancer.

Bortezomib which inhibits the proteolytic activity of the proteasome is used for the treatment of multiple myeloma and relapsed mantle cell lymphoma.  We are looking at the therapeutic potential and biochemical consequences of alternative mechanisms of targeting the proteasome, including the suppression of components of the 19S regulatory particle of the proteasome and ubiquitin receptors involved in proteasomal recruitment.  This is important because targeting the proteasome in alternative ways can have different effects on cellular pathways [5]. 

We also intend to carry out siRNA screens in the SCILLS screening facility (College of Life Sciences, University of Dundee) to identify additional components of the ubiquitin system which could be targeted for cancer therapy.  The therapeutic potential and the cellular roles of the proteins identified in the screens will be investigated. 

We are particularly focused on applying our work to the treatment of cutaneous squamous cell carcinoma (cSCC).  There is a need for the development of improved therapies for cSCC [6].  This cancer is very common and the incidence is increasing.  In the UK, around 1 in 4 skin cancer deaths are due to cSCC.  Patients with regional metastasis have a 5-year survival rate of 25–50%.  High risk groups exist.  Immunosuppressed organ transplant recipients have more than a 100-fold increased risk of developing cSCC.  In addition, 80% of deaths in patients with the genetic skin-blistering disease recessive dystrophic epidermolysis bullosa (RDEB) are due to cSCC.  

References

1.         Allende-Vega N, Saville MK. Targeting the ubiquitin-proteasome system to activate wild-type p53 for cancer therapy. Semin Cancer Biol 2010; 20: 29-39.

2.         Allende-Vega N, Sparks A, Lane DP, Saville MK. MdmX is a substrate for the deubiquitinating enzyme USP2a. Oncogene 2010; 29: 432-441.

3.         Dayal S, Sparks A, Jacob J et al. Suppression of the deubiquitinating enzyme USP5 causes the accumulation of unanchored polyubiquitin and the activation of p53. J Biol Chem 2009; 284: 5030-5041.

4.         Stevenson LF, Sparks A, Allende-Vega N et al. The deubiquitinating enzyme USP2a regulates the p53 pathway by targeting Mdm2. Embo J 2007; 26: 976-986.

5.         Sparks A, Menendez S, Saville MK. The degradation of p53 and its major E3 ligase Mdm2 is differentially dependent on the intrinsic proteasomal ubiquitin receptor S5a  Manuscript under review.

6.         Bonerandi JJ, Beauvillain C, Caquant L et al. Guidelines for the diagnosis and treatment of cutaneous squamous cell carcinoma and precursor lesions. J Eur Acad Dermatol Venereol 2011; 25 Suppl 5: 1-51.

 

Supervisor: 
Dr Mark Saville
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