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Background: Human hepatocellular carcinoma (HCC) is a common liver tumor and the main cause of cancer-related death. Tyrosine kinase inhibitors, such as imatinib and GNF5 which were developed to treat chronic myelogenous leukemia, regulate the progression of various cancers. The aim of this study was to confirm the anti-tumor activity of tyrosine kinase inhibitors through regulation of S-phase kinase-associated protein 2 (Skp2), an important oncogenic factor in various cancer cells, in human hepatocarcinoma SK-HEP1 cells. Methods: Cell viability and colony formation assays were conducted to evaluate the effects of imatinib, GNF5 and GNF2 on the growth of SK-HEP1 cells. Using immunoblot analysis, we assessed change of the activation of caspases, PARP, Akt, mitogen-activated protein kinases, and Skp2/p27/p21 pathway by imatinib and GNF5 in SK-HEP1 cells. Using sh-Skp2 HCC cells, the role of Skp2 in the effects of imatinib and GNF5 was evaluated. Results: Imatinib and GNF5 significantly inhibited the growth of SK-HEP1 cells. Treatment of imatinib and GNF5 decreased Skp2 expression and Akt phosphorylation, and increased the expression of p27, p21, and active-caspases in SK-HEP1 cells. In sh-Skp2 HCC cells, cell growth and the expression of Skp2 were inhibited by more than in the mock group treated with imatinib and GNF5. Conclusions: These results suggest that the anti-growth activity of tyrosine kinase inhibitors may be associated with the regulation of p27/p21 and caspases through Skp2 blockage in HCC cells. (J Cancer Prev 2018;23:170-175)
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참고문헌 (23)
참고문헌 신청
Forner A / 2012 / Hepatocellular carcinoma / Lancet 379:1245~1255
Di Maio M / 2002 / Hepatocellular carcinoma: systemic treatments / J Clin Gastroenterol 35:S109~S114
Le Grazie M / 2017 / Chemotherapy for hepatocellular carcinoma: the present and the future / World J Hepatol 9:907~920
Frescas D / 2008 / Deregulated proteolysis by the F-box proteins SKP2 and beta-TrCP: tipping the scales of cancer / Nat Rev Cancer 8:438~449
Nakayama K / 2000 / Targeted disruption of Skp2 results in accumulation of cyclin E and p27(Kip1), polyploidy and centrosome overduplication / EMBO J 19:2069~2081
Di Maio M / 2002 / Hepatocellular carcinoma: systemic treatments / J Clin Gastroenterol 35:S109~S114
Le Grazie M / 2017 / Chemotherapy for hepatocellular carcinoma: the present and the future / World J Hepatol 9:907~920
Frescas D / 2008 / Deregulated proteolysis by the F-box proteins SKP2 and beta-TrCP: tipping the scales of cancer / Nat Rev Cancer 8:438~449
Nakayama K / 2000 / Targeted disruption of Skp2 results in accumulation of cyclin E and p27(Kip1), polyploidy and centrosome overduplication / EMBO J 19:2069~2081
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