title: Bortezomib stabilizes mitotic cyclins and prevents cell cycle progression via inhibition of UBE2C in colorectal carcinoma.
abstract: Substantial evidence implicates the ubiquitin-conjugating enzyme E2C (UBE2C) gene, in several human cancers, including colorectal carcinoma (CRC). We therefore investigated the prognostic value of UBE2C alterations in CRC and UBE2C signaling in CRC cell lines. UBE2C protein expression and UBE2C gene copy number were evaluated on clinical samples by immunohistochemistry and fluorescence in situ hybridization in a TMA format. The effect of the proteasome inhibitor bortezomib and small-interfering RNA knockdown was assessed by apoptotic assays and immunoblotting. UBE2C dysregulation was associated with proliferative marker Ki-67, accumulation of cyclin A and B1, and a poor overall survival. UBE2C expression was an independent prognostic marker in early-stage (I and II) CRC. UBE2C depletion resulted in suppression of cellular growth and accumulation of cyclin A and B1. In vitro, bortezomib treatment of CRC cells caused inhibition of cell viability via down-regulation of UBE2C. UBE2C knockdown by bortezomib or transfection with specific small-interfering RNA against UBE2C also caused cells to be arrested at the G2/M level, leading to accumulation of cyclin A and cyclin B1. In vivo, a significant reduction in tumor volume and weight was noted in mice treated with a combination of subtoxic doses of oxaliplatin and bortezomib compared with treatment with oxaliplatin or bortezomib alone. Altogether, our results suggest that UBE2C and the ubiquitin-proteasome pathway may be potential targets for therapeutic intervention in CRC.
authors.affiliation: Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Prashant
authors.initials: P
authors.lastname: Bavi
authors.forename: Shahab
authors.initials: S
authors.lastname: Uddin
authors.forename: Maqbool
authors.initials: M
authors.lastname: Ahmed
authors.forename: Zeenath
authors.initials: Z
authors.lastname: Jehan
authors.forename: Rong
authors.initials: R
authors.lastname: Bu
authors.forename: Jehad
authors.initials: J
authors.lastname: Abubaker
authors.forename: Mehar
authors.initials: M
authors.lastname: Sultana
authors.forename: Nasser
authors.initials: N
authors.lastname: Al-Sanea
authors.forename: Alaa
authors.initials: A
authors.lastname: Abduljabbar
authors.forename: Luai H
authors.initials: LH
authors.lastname: Ashari
authors.forename: Samar
authors.initials: S
authors.lastname: Alhomoud
authors.forename: Fouad
authors.initials: F
authors.lastname: Al-Dayel
authors.forename: Sarita
authors.initials: S
authors.lastname: Prabhakaran
authors.forename: Azhar R
authors.initials: AR
authors.lastname: Hussain
authors.forename: Khawla S
authors.initials: KS
authors.lastname: Al-Kuraya
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000032:analysis; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002453:Cell Cycle / Q000187:drug effects* / Q000502:physiology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016213:Cyclins / Q000187:drug effects / Q000378:metabolism; D018628:Gene Dosage; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D008819:Mice, Nude; D011379:Prognosis; D011719:Pyrazines / Q000494:pharmacology*; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046888:Tissue Array Analysis; D044763:Ubiquitin-Conjugating Enzymes / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D001897:Boronic Acids; D016213:Cyclins; D011719:Pyrazines; D034741:RNA, Small Interfering; D000069286:Bortezomib; C105156:UBE2C protein, human; D044763:Ubiquitin-Conjugating Enzymes