Cilostazol Induces Apoptosis and Inhibits Proliferation of Hepatocellular Carcinoma Cells by Activating AMPK

• Published in: Biotechnology and bioprocess engineering 2021, 26(5), , pp.776-785
• Main Authors: Sim, Kyeong Hwa, Shu, Mi-Sun, Kim, Soyoung, Kim, Jong-Yeon, Choi, Bo-Hyun, Lee, Youn Ju
• Format: Article
• Language: English
• Subjects: AKT protein; AMP-activated protein kinase; Anticancer properties; Antigens; Antiproliferatives; Antitumor agents; Apoptosis; Biotechnology; Cell activation; Cell cycle; Cell death; Cell proliferation; Chemistry; Chemistry and Materials Science; Colon; Colon cancer; Crosstalk; Cyclin D1; Extracellular signal-regulated kinase; Hepatectomy; Hepatocellular carcinoma; Hepatocytes; Industrial and Production Engineering; Kinases; Liver cancer; Proliferating cell nuclear antigen; Regeneration; Research Paper; Signaling; siRNA; Squamous cell carcinoma; Tumors; 생물공학
• ISSN: 1226-8372; 1976-3816
• DOI: 10.1007/s12257-021-0002-8

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 G 0 /G 1 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.