Overexpression of eukaryotic elongation factor eEF2 in gastrointestinal cancers and its involvement in G2/M progression in the cell cycle.
A high level protein synthesis is one of the characteristics of cancer cells. The aim of this study is to show the contribution of eukaryotic elongation factor 2 (eEF2), which plays an essential role in the polypeptide chain elongation step, in the tumorigenesis of gastrointestinal cancers. In the present study, we demonstrated by using immunohistochemistry that eEF2 protein was overexpressed in 92.9% (13 of 14) of gastric and 91.7% (22 of 24) of colorectal cancers. No mutations were found in any of the exons of the eEF2 gene in six gastric and six colorectal cancers. Knockdown of eEF2 by eEF2-specific short-hairpin RNA (shEF2) inhibited cancer cell growth in two gastric cancer cell lines, AZ-521 and MKN28, and one colon cancer cell line, SW620. Flow cytometric analysis showed that knockdown of eEF2 induced G2/M arrest and resulted in inactivation of Akt and cdc2 (a G2/M regulator) and activation of eEF2 kinase (a negative regulator of eEF2) in these cancer cells. Conversely, forced expression of eEF2 in AZ-521 cells significantly enhanced the cell growth through promotion of G2/M progression in cell cycle, activated Akt and cdc2, and inactivated eEF2 kinase. Furthermore, forced expression of eEF2 in these cancer cells enhanced in vivo tumorigenicity in a mouse xenograft model. These results showed that overexpressed eEF2 in gastrointestinal cancers promoted G2/M progression and enhanced their cell growth in vitro and in vivo. These results also suggested a novel linkage between translational elongation and cell cycle mechanisms, implying that the linkage might play an important role to orchestrate the deregulated translation and cell cycle mechanisms for promotion of the development of gastrointestinal cancers.
Nakamura
Junya
J
Department of Functional Diagnostic Science, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
Aoyagi
Sayaka
S
Nanchi
Isamu
I
Nakatsuka
Shin-Ichi
S
Hirata
Erika
E
Shibata
Shohei
S
Fukuda
Mari
M
Yamamoto
Yumiko
Y
Fukuda
Ikuyo
I
Tatsumi
Naoya
N
Ueda
Tazu
T
Fujiki
Fumihiro
F
Nomura
Masaya
M
Nishida
Sumiyuki
S
Shirakata
Toshiaki
T
Hosen
Naoki
N
Tsuboi
Akihoro
A
Oka
Yoshihiro
Y
Nezu
Riichiro
R
Mori
Masaki
M
Doki
Yuichiro
Y
Aozasa
Katsuyuki
K
Sugiyama
Haruo
H
Oji
Yusuke
Y
D000230:Adenocarcinoma / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D002455:Cell Division / Q000235:genetics*; D005260:Female; D016195:G2 Phase / Q000235:genetics*; D005770:Gastrointestinal Neoplasms / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D008954:Models, Biological; D020652:Peptide Elongation Factor 2 / Q000235:genetics*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D055815:Young Adult
D020652:Peptide Elongation Factor 2