title: Targeting the 19S proteasomal subunit, Rpt4, for the treatment of colon cancer.
abstract: 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.
authors.affiliation: Centre for Systems Medicine and Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St Stephen's Green, Dublin 2, Ireland; Department of Gastroenterology, Beaumont Hospital, Beaumont, Dublin 9, Ireland.
authors.forename: Karen
authors.initials: K
authors.lastname: Boland
authors.affiliation: Centre for Systems Medicine and Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St Stephen's Green, Dublin 2, Ireland.
authors.forename: Lorna
authors.initials: L
authors.lastname: Flanagan
authors.affiliation: Centre for Systems Medicine and Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St Stephen's Green, Dublin 2, Ireland; Department of Surgery, Beaumont Hospital, Beaumont, Dublin 9, Ireland.
authors.forename: Niamh
authors.initials: N
authors.lastname: McCawley
authors.affiliation: School of Pharmacy, Royal College of Surgeons in Ireland, York House, York Street, Dublin 2, Ireland.
authors.forename: Ritesh
authors.initials: R
authors.lastname: Pabari
authors.affiliation: Department of Pathology, Beaumont Hospital, Beaumont, Dublin 9, Ireland.
authors.forename: Elaine W
authors.initials: EW
authors.lastname: Kay
authors.affiliation: Department of Surgery, Beaumont Hospital, Beaumont, Dublin 9, Ireland.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: McNamara
authors.affiliation: Department of Gastroenterology, Beaumont Hospital, Beaumont, Dublin 9, Ireland.
authors.forename: Frank
authors.initials: F
authors.lastname: Murray
authors.affiliation: Centre for Systems Medicine and Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St Stephen's Green, Dublin 2, Ireland.
authors.forename: Annette T
authors.initials: AT
authors.lastname: Byrne
authors.affiliation: School of Pharmacy, Royal College of Surgeons in Ireland, York House, York Street, Dublin 2, Ireland.
authors.forename: Zebunnissa
authors.initials: Z
authors.lastname: Ramtoola
authors.affiliation: Centre for Systems Medicine and Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St Stephen's Green, Dublin 2, Ireland.
authors.forename: Caoimhín G
authors.initials: CG
authors.lastname: Concannon
authors.affiliation: Centre for Systems Medicine and Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St Stephen's Green, Dublin 2, Ireland. Electronic address: jprehn@rcsi.ie.
authors.forename: Jochen H M
authors.initials: JH
authors.lastname: Prehn
mesh_terms: D017209:Apoptosis / Q000235:genetics; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000628:therapy*; D004337:Drug Carriers / Q000737:chemistry; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D045325:HCT116 Cells; D006801:Humans; D058990:Molecular Targeted Therapy; D053758:Nanoparticles / Q000737:chemistry; D046988:Proteasome Endopeptidase Complex / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000737:chemistry / Q000235:genetics; D017211:Treatment Failure
chemical_list: D004337:Drug Carriers; D034741:RNA, Small Interfering; D046988:Proteasome Endopeptidase Complex
keywords: Chemotherapy; Colorectal cancer; Nanocomplexes; Proteasome; Rpt4