Expression and Effect of Inhibition of the Ubiquitin-Conjugating Enzyme E2C on Esophageal Adenocarcinoma

Abstract

Ubiquitin-dependent proteolysis of cyclins plays a critical role in cell cycle progression and tumorigenesis. We examined the expression of ubiquitin-conjugating enzyme E2C (UBE2C) during progression from Barrett's metaplasia to esophageal adenocarcinoma (EA) and the effects of targeting this enzyme on EA-derived cell lines. Using oligonucleotide microarrays UBE2C expression was elevated in 73% (11 of 15) of EAs relative to Barrett's metaplasia. Tissue microarray showed elevated UBE2C in 70% (7 of 10) of dysplastic samples and in 87% (58 of 67) of tumors relative to metaplastic samples. Transfection of dominant-negative UBE2C into Seg-1 cells decreased proliferation (P = .04) and increased mitotic arrest compared to vector controls (63.5% vs 6.8%; P < .001). Transfection of UBE2C small interfering RNA also caused inhibiton of cell proliferation and distortion of the cell cycle, with maximal increase of G(2) cells (155% of mock cells) at 72 hours and of S-phase cells (308% of mock cells) at 24 hours. Treatment of Seg-1 cells with the proteasome inhibitor MG-262 (1 nM-1 microM) showed decreased proliferation (P = .02). EA-derived cells expressing UBE2C are sensitive to treatment with MG-262 and to silencing of UBE2C, suggesting that patients with EAs overexpressing UBE2C may benefit from agents targeting this ubiquitin-conjugating enzyme.

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

“…Similar paradoxical direct associations between UBE2C and cyclin B1 have been reported in lymphomas. 33 Although no specific UBE2C inhibitors are currently available for clinical use, Lin et al 10 have shown that treatment of esophageal adenocarcinoma cells with MG-262, a proteasome inhibitor, caused a significant downregulation of UBE2C accompanied by inhibition in cell proliferation and accumulation of cyclin A and B1. We have recently shown that bortezomib, another proteasome inhibitor, suppressed the growth and reduced cell viability in a number of cancer cells both in vitro and in vivo.…”

“…These findings are in agreement with an earlier study in which esophageal adenocarcinoma cells strongly expressing UbcH10 were highly sensitive to treatment with the proteasome inhibitor MG-262. 10 Results of previous bortezomib clinical trials either alone or in combination (oxaliplatin, leucovorin, and 5-fluorouracil with fluorouracil/leucovorin or irinotecan) in the setting of advanced CRC are not encouraging. [35][36][37] However, using bortezomib in combination with other biological agents through an understanding of its effects on different signaling pathways may prove more fruitful.…”

“…10 Furthermore, depletion of UBE2C resulted in accumulation of cyclin A and B1. 32 We, therefore, sought to determine whether treatment of CRC cells with bortezomib modulates the accumulation of cyclins in CRC cells.…”

“…3,6 Overexpression of UBE2C at the mRNA level has been reported in a number of cancer cell lines and primary tumors, whereas only low levels were found in normal tissues. 7 The oncogenic role of UBE2C is also reported in thyroid, 8 ovarian, 9 esopha-geal, 10 breast, 11 lung, 12 liver, 13 and brain 14 tumors. Takahashi et al 15 suggest that overexpression of UBE2C may play an important role in advanced colon cancer with liver metastases and that this overexpression may be a result of chromosomal amplification at the UBE2C locus, 20q13.1.…”

High expression of UBE2C is associated with the aggressive progression and poor outcome of malignant glioma

“…Ubiquitin-conjugating enzyme E2C (UBE2C) belongs to the E2 family, and is involved in mitotic cyclin destruction and cell cycle progression (8). UBE2C has been implicated in the carcinogenesis of certain tumors (9,10), and is overexpressed in various human cancers, including breast, esophageal, colon, lung, liver and ovarian cancers (11)(12)(13)(14)(15)(16).…”