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Journal of Cancer Prevention

Original Article

J Cancer Prev 2020; 25(4): 252-257

Published online December 30, 2020

https://doi.org/10.15430/JCP.2020.25.4.252

© Korean Society of Cancer Prevention

Imatinib and GNF-5 Exhibit an Inhibitory Effect on Growth of Hepatocellar Carcinoma Cells by Downregulating S-phase Kinase-associated Protein 2

Haibo Zhang1 ,*, Junkoo Yi2 ,*, Duhak Yoon1 , Zaeyoung Ryoo3 , Inkyu Lee4 , Myoungok Kim1

1Department of Animal Science and Biotechnology, Kyungpook National University, Sangju, 2Gyeongsangbukdo Livestock Institute Research, Yeongju, 3School of Life Science, Kyungpook National University, 4Departments of Internal Medicine, Biochemistry and Cell Biology, Kyungpook National University School of Medicine, Daegu, Korea

Correspondence to :
Myoungok Kim, E-mail: ok4325@knu.ac.kr, https://orcid.org/0000-0001-6650-7734
*These authors contributed equally to this work as co-first authors.

Received: August 28, 2020; Revised: November 18, 2020; Accepted: November 21, 2020

Abstract

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is one of the leading causes of cancer-related deaths worldwide. Imatinib and GNF-5 are breakpoint cluster region-Abelson murine leukemia tyrosine kinase inhibitors which have been approved for the treatment of chronic myeloid leukemia and various solid tumors. However, the effect and underlying mechanisms of imatinib and GNF-5 in HCC remain poorly defined. In this study, we investigated the anticancer activity and underlying mechanisms of imatinib and GNF-5 in HepG2 human hepatocarcinoma cells. Cell proliferation and anchorage-independent colony formation assays were done to evaluate the effects of imatinib and GNF-5 on the growth of HepG2 cells. The cell cycle was assessed by flow cytometry and verified by immunoblot analysis. Gene overexpression and knockdown assays were conducted to evaluate the function of S-phase kinase-associated protein 2 (Skp2). Imatinib and GNF-5 significantly inhibited the growth of HepG2 cells. Imatinib and GNF-5 induced G0/G1 phase cell cycle arrest by downregulating Skp2 and upregulating p27 and p21. Overexpression of Skp2 reduced the effect of imatinib and GNF-5 on HepG2 cells. Knockdown of Skp2 suppressed the proliferation and induced G0/G1 phase arrest. Furthermore, knockdown of Skp2 enhanced the effect of imatinib and GNF-5 on growth of HepG2 cells. In conclusion, imatinib and GNF-5 effectively suppress HepG2 cell growth by inhibiting Skp2 expression. Skp2 promotes the cell proliferation and reverse G0/G1 phase cell cycle arrest and it represents a potential therapeutic target for HCC treatment.

Keywords: Hepatocellular carcinoma, Cell cycle, S-phase kinase-associated protein 2, Imatinib, GNF-5

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