Abstract
Hepatocellular carcinoma (HCC) is the most prevalent subtype of liver cancer with a mortality rate of approximately 3–6/100,000 and is the third leading cause of cancer-related death worldwide. Although several small-molecule drugs have been developed for the treatment of HCC, the choice of an agent for patients who require systemic chemotherapy at an advanced stage is still limited. The Hippo pathway is an evolutionarily conserved tumor suppressive pathway commonly dysregulated in HCC, which makes it a promising target for anti-HCC therapies. Homoharringtonine (HHT) is an FDA-approved anti-leukemia drug with proven strong anti-tumor activity in solid tumors. In this study, we found that HHT could significantly inhibit HCC cell growth by suppressing cell proliferation and colony formation. Moreover, HHT repressed cell invasion and migration remarkably. Additionally, HHT induced cell cycle arrest at S phase and promoted apoptosis. Most importantly, we showed that HHT-induced apoptosis was a consequence of the Hippo pathway activation. Consistently, the MST1/2 inhibitor, XMU-MP-1, could restore cell viability and reverse HHT-induced cell apoptosis. Furthermore, in vivo results confirmed the tumor inhibitory effect of HHT. Taken together, our findings suggest that HHT is a potential alternative therapeutic agent for the treatment of HCC.
Highlights
Primary liver cancer is currently the fourth most common malignant tumor and the third cause of cancer-related death worldwide (Bertuccio et al, 2017)
The results demonstrate that HHT suppresses proliferation of Hepatocellular carcinoma (HCC) cells
HCC incidence has shown a global upward trend over the last decade (Bertuccio et al, 2017), with approximately over 60% patients at an intermediate or advanced stage when newly diagnosed (Yang et al, 2019). For this portion of patients, transarterial chemoembolization (TACE) or systemic treatment combined with targeted molecular inhibitors would yield better outcomes; for instance, multi-targeted tyrosine kinase inhibitors (TKIs) such as sorafenib and lenvatinib have benefited patients with advanced and unresectable HCC (Forner et al, 2018; Yamada et al, 2020; Yoo et al, 2020; Zhao et al, 2020)
Summary
Primary liver cancer is currently the fourth most common malignant tumor and the third cause of cancer-related death worldwide (Bertuccio et al, 2017). It includes mainly hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), and HCC-ICC mixed type, among which HCC accounts for about 85–90% of cases, with a mortality rate of about 3–6/100,000 (Bertuccio et al, 2017). HCC is usually resistant to chemotherapeutic agents in TACE or system chemotherapy (Bruix et al, 2016). More efficient new agents should be introduced into the treatment of HCC
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