Akt‑dependent activation of Erk by cyclin D1b contributes to cell invasiveness and tumorigenicity

Kim,Chul Jang; Tambe,Yukihiro; Mukaisho,Ken‑Ichi; Sugihara,Hiroyuki; Kawauchi,Akihiro; Inoue,Hirokazu

doi:10.3892/ol.2016.5286

Akt‑dependent activation of Erk by cyclin D1b contributes to cell invasiveness and tumorigenicity

Authors:
- Chul Jang Kim
- Yukihiro Tambe
- Ken‑Ichi Mukaisho
- Hiroyuki Sugihara
- Akihiro Kawauchi
- Hirokazu Inoue
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Affiliations: Department of Urology, Kohka Public Hospital, Kohka, Shiga 528‑0014, Japan, Division of Microbiology and Infectious Diseases, Shiga University of Medical Science, Otsu, Shiga 520‑2192, Japan, Division of Molecular and Diagnostic Pathology, Shiga University of Medical Science, Otsu, Shiga 520‑2192, Japan, Department of Urology, Shiga University of Medical Science, Otsu, Shiga 520‑2192, Japan
Published online on: October 18, 2016 https://doi.org/10.3892/ol.2016.5286
Pages: 4850-4856

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Abstract

A total of two major isoforms, cyclin D1a and cyclin D1b, are generated from the human cyclin D1 gene by alternative splicing. Cyclin D1b is scarcely expressed in normal tissues; however, it is expressed at a high frequency in certain types of cancerous tissue. The present authors previously constructed cyclin D1b transgenic (Tg) mice and identified rectal tumors, including adenocarcinoma and sessile serrated adenoma, in 62.5% of female Tg mice. In addition, the present authors indicated that cyclin D1b expression enhances phosphorylation of extracellular signal‑regulated kinase (Erk) in these rectal tumors, and in mouse embryonic fibroblast (MEF) cells and human 293T cells. In the present study, it was initially demonstrated that cyclin D1b has the ability to enhance cell invasiveness by itself; it additionally increases cell invasiveness, anchorage‑independent growth and tumorigenicity in cooperation with an activated K‑ras oncogene in MEF cells. Phosphorylation of Akt was increased in cyclin D1b‑expressing MEF cells and in the rectal tumor tissues of cyclin D1b Tg mice. Phosphorylation of Akt was also enhanced by transfection of cyclin D1b, but not cyclin D1a, in human 293T cells. Treatment with an Akt inhibitor suppressed phosphorylation of Erk in 293T cells expressing cyclin D1b and D1bTgRT cells established from rectal cancer of the cyclin D1b Tg mouse. Furthermore, the Akt inhibitor suppressed the invasiveness of D1bTgRT cells and the tumor growth of these cells in nude mice when the Akt inhibitor was injected into the tumors. These results indicate that cyclin D1b activates Erk through Akt, and that activation of Akt contributes to the tumorigenicity of the cyclin D1b Tg mice. Inhibitors targeting the phosphoinositide 3‑kinase/Akt signaling pathway are thus expected to have therapeutic potential in a variety of human cancer types expressing cyclin D1b.

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