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KMID : 1094720210260050776
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Biotechnology and Bioprocess Engineering
2021 Volume.26 No. 5 p.776 ~ p.785
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Cilostazol Induces Apoptosis and Inhibits Proliferation of Hepatocellular Carcinoma Cells by Activating AMPK
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Sim Kyeong-Hwa
Shu Mi-Sun
Kim So-Young
Kim Jong-Yeon
Choi Bo-Hyun
Lee Youn-Ju
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Abstract
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Hepatocellular carcinoma (HCC) is the most common primary liver cancer and one of the leading causes of cancer-related death. Cilostazol, an antiplatelet drug, elicits anticancer effects on human squamous cell carcinoma and colon cancer cells. We previously reported that cilostazol protects normal mature hepatocytes from alcohol-induced apoptotic cell death. In addition, cilostazol stimulates liver regeneration after hepatectomy. Therefore, this study evaluated whether cilostazol elicits pro- or anti-proliferative effects on HCC using Hep3B and SK-Hep1 cells. Cilostazol inhibited proliferation of HCC cells by inducing apoptosis. Additionally, cilostazol induced G0/G1 cell cycle arrest and decreased expression of cyclin D1 and proliferating cell nuclear antigen. Activation of AMP-activated protein kinase (AMPK) and inhibition of extracellular signal-regulated kinase (ERK) and AKT signaling were associated with the anti-proliferative effect of cilostazol. LY294002 and PD98059, inhibitors of AKT and ERK, respectively, enhanced the anti-proliferative effect of cilostazol. By contrast, inhibition of AMPK using compound C or AMPK-targeting siRNA abolished the anti-proliferative effect of cilostazol. Moreover, AMPK inhibition reversed the down-regulation of AKT/EKR induced by cilostazol, indicating negative cross-talk between AMPK and AKT/ERK. These findings provide evidence that cilostazol exerts anti-tumor activity in HCC by counter-regulating AMPK and AKT/ERK signaling. Taken together, our findings suggest that cilostazol may provide clinical benefits in HCC patients by selectively targeting HCC cells without interfering with liver function.
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KEYWORD
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cilostazol, hepatocellular carcinoma, apoptosis, AMPK, ERK, AKT
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