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Targeting the 19S proteasomal subunit, Rpt4, for the treatment of colon cancer.

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posted on 22.11.2019 by Karen Boland, Lorna Flanagan, Niamh McCawley, Ritesh Pabari, Elaine W. Kay, Deborah A. McNamara, Frank Murray, Annette Byrne, Zebunnissa Ramtoola, Caoimhín Concannon, Jochen Prehn

Deregulation of the ubiquitin-proteasome pathway has been frequently observed in a number of malignancies. Using quantitative Western blotting of normal and matched tumour tissue, we here identified a significant increase in the 19S proteasome subunit Rpt4 in response to chemoradiation in locally advanced rectal cancer patients with unfavourable outcome. We therefore explored the potential of Rpt4 reduction as a therapeutic strategy in colorectal cancer (CRC). Utilizing siRNA to down regulate Rpt4 expression, we show that silencing of Rpt4 reduced proteasomal activity and induced endoplasmic reticulum stress. Gene silencing of Rpt4 also inhibited cell proliferation, reduced clonogenic survival and induced apoptosis in HCT-116 colon cancer cells. We next developed a cell penetrating peptide-based nanoparticle delivery system to achieve in vivo gene silencing of Rpt4. Administration of Rpt4 siRNA nanoparticles reduced tumour growth and improved survival in a HCT-116 colon cancer xenograft tumour model in vivo. Collectively, our data suggest that inhibition of Rpt4 represents a novel strategy for the treatment of CRC.

Funding

This research was supported by grants from the Health Research Board, Ireland (APOCOLON; TRA/2007/26; HRA_POR/2012/121) to JHMP, EWK and FM, and ScienceFoundation Ireland (13/IA/1881) to JHMP.

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Published Citation

Boland K, Flanagan L, McCawley N, Pabari R, Kay EW, McNamara DA, Murray F, Byrne AT, Ramtoola Z, Concannon CG, Prehn JHM. Targeting the 19S proteasomal subunit, Rpt4, for the treatment of colon cancer. European Journal of Pharmacology. 2016; 780:53-64.

Publication Date

17/03/2016

Publisher

Elsevier Science

PubMed ID

26997367

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