Bortezomib Stabilizes Mitotic Cyclins and Prevents Cell Cycle Progression via Inhibition of UBE2C in Colorectal Carcinoma

被引：61

作者：

Bavi, Prashant ^{[1
]}

Uddin, Shahab ^{[1
]}

Ahmed, Maqbool ^{[1
]}

Jehan, Zeenath ^{[1
]}

Bu, Rong ^{[1
]}

Abubaker, Jehad ^{[1
]}

Sultana, Mehar ^{[1
]}

Al-Sanea, Nasser ^{[3
]}

Abduljabbar, Alaa ^{[3
]}

Ashari, Luai H. ^{[3
]}

Alhomoud, Samar ^{[3
]}

Al-Dayel, Fouad ^{[2
]}

Prabhakaran, Sarita ^{[1
]}

Hussain, Azhar R. ^{[1
]}

Al-Kuraya, Khawla S. ^{[1
]}

机构：

[1] King Faisal Specialist Hosp & Res Ctr, Human Canc Genom Res Ctr, Res Ctr, Riyadh 11211, Saudi Arabia

[2] King Faisal Specialist Hosp & Res Ctr, Dept Surg, Colorectal Sect, Riyadh 11211, Saudi Arabia

[3] King Faisal Specialist Hosp & Res Ctr, Dept Pathol, Riyadh 11211, Saudi Arabia

来源：

AMERICAN JOURNAL OF PATHOLOGY | 2011年 / 178卷 / 05期

关键词：

UBIQUITIN-CONJUGATING ENZYME; PHASE KINASE PROTEIN-2; PROTEASOME INHIBITOR; UBCH10; EXPRESSION; THERAPEUTIC TARGET; COLON-CANCER; OVEREXPRESSION; DEGRADATION; TOOL; 5-FLUOROURACIL;

D O I：

10.1016/j.ajpath.2011.01.034

中图分类号：

R36 [病理学];

学科分类号：

100104 ;

摘要：

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 sub-toxic 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. (AmJ Pathol 2011, 178: 2109-2120; DOI: 10.1016/j.ajpath.2011.01.034)

引用

页码：2109 / 2120

页数：12