CGK062, a small chemical molecule, inhibits cancer upregulated gene 2‑induced oncogenesis through NEK2 and β‑catenin

Kaowinn,Sirichat; Oh,Sangtaek; Moon,Jeong; Yoo,Ah Young; Kang,Ho Young; Lee,Mi Rim; Kim,Ji Eun; Hwang,Dae Youn; Youn,So Eun; Koh,Sang Seok; Chung,Young‑Hwa

doi:10.3892/ijo.2019.4724

CGK062, a small chemical molecule, inhibits cancer upregulated gene 2‑induced oncogenesis through NEK2 and β‑catenin

Authors:
- Sirichat Kaowinn
- Sangtaek Oh
- Jeong Moon
- Ah Young Yoo
- Ho Young Kang
- Mi Rim Lee
- Ji Eun Kim
- Dae Youn Hwang
- So Eun Youn
- Sang Seok Koh
- Young‑Hwa Chung
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Affiliations: BK21 Plus, Department of Cogno‑Mechatronics Engineering, Pusan National University, Busan 46241, Republic of Korea, Department of Bio and Fermentation Convergence Technology, Kookmin University, Seoul 02707, Republic of Korea, Department of Microbiology, Pusan National University, Busan 46241, Republic of Korea, Department of Biomaterials, Pusan National University, Miryang 50463, Republic of Korea, Department of Biosciences, Dong‑A University, Busan 49315, Republic of Korea
Published online on: February 22, 2019 https://doi.org/10.3892/ijo.2019.4724
Pages: 1295-1305
Copyright: © Kaowinn et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The mechanisms through which cancer‑upregulated gene 2 (CUG2), a novel oncogene, affects Wnt/β‑catenin signaling, essential for tumorigenesis, are unclear. In this study, we aimed to elucidate some of these mechanisms in A549 lung cancer cells. Under the overexpression of CUG2, the protein levels and activity of β‑catenin were evaluated by western blot analysis and luciferase assay. To examine a biological consequence of β‑catenin under CUG2 overexpression, cell migration, invasion and sphere formation assay were performed. The upregulation of β‑catenin induced by CUG2 overexpression was also accessed by xenotransplantation in mice. We first found that CUG2 overexpression increased β‑catenin expression and activity. The suppression of β‑catenin decreased cancer stem cell (CSC)‑like phenotypes, indicating that β‑catenin is involved in CUG2‑mediated CSC‑like phenotypes. Notably, CUG2 overexpression increased the phosphorylation of β‑catenin at Ser33/Ser37, which is known to recruit E3 ligase for β‑catenin degradation. Moreover, CUG2 interacted with and enhanced the expression and kinase activity of never in mitosis gene A‑related kinase 2 (NEK2). Recombinant NEK2 phosphorylated β‑catenin at Ser33/Ser37, while NEK2 knockdown decreased the phosphorylation of β‑catenin, suggesting that NEK2 is involved in the phosphorylation of β‑catenin at Ser33/Ser37. Treatment with CGK062, a small chemical molecule, which promotes the phosphorylation of β‑catenin at Ser33/Ser37 through protein kinase C (PKC)α to induce its degradation, reduced β‑catenin levels and inhibited the CUG2‑induced features of malignant tumors, including increased cell migration, invasion and sphere formation. Furthermore, CGK062 treatment suppressed CUG2‑mediated tumor formation in nude mice. Taken together, the findings of this study suggest that CUG2 enhances the phosphorylation of β‑catenin at Ser33/Ser37 by activating NEK2, thus stabilizing β‑catenin. CGK062 may thus have potential for use as a therapeutic drug against CUG2‑overexpressing lung cancer cells.

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