Homoharringtonine Exerts Anti-tumor Effects in Hepatocellular Carcinoma Through Activation of the Hippo Pathway.
Homoharringtonine Exerts Anti-tumor Effects in Hepatocellular Carcinoma Through Activation of the Hippo Pathway.
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高三尖杉酯碱通过激活 Hippo 通路在肝细胞癌中发挥抗肿瘤作用
DOI：
10.3389/fphar.2021.592071
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发表时间：
2021
影响因子：
5.6
通讯作者：
Yan J
中科院分区：
文献类型：
--
作者：
Wang H;Wang R;Huang D;Li S;Gao B;Kang Z;Tang B;Xie J;Yan F;Liang R;Li H;Yan J
肝细胞癌（HCC）是最常见的肝癌亚型，死亡率约为3-6/100，000，并且是全世界癌症相关死亡的第三大原因。虽然已经开发了几种小分子药物用于治疗HCC，但对于需要全身化疗的晚期患者来说，药物的选择仍然有限。Hippo通路是一种进化上保守的肿瘤抑制通路，通常在HCC中失调，这使其成为抗HCC治疗的有希望的靶点。高三尖杉酯碱（HHT）是FDA批准的抗白血病药物，在实体瘤中具有较强的抗肿瘤活性。在本研究中，我们发现HHT可以通过抑制细胞增殖和集落形成来显著抑制肝癌细胞的生长。HHT还能显著抑制细胞的侵袭和迁移。此外，HHT诱导细胞周期停滞在S期，并促进凋亡。最重要的是，我们发现HHT诱导的细胞凋亡是Hippo通路激活的结果。结论：MST 1/2抑制剂XMU-MP-1可恢复HHT诱导的细胞活力，逆转HHT诱导的细胞凋亡。此外，体内实验结果证实了HHT的肿瘤抑制作用。总之，我们的研究结果表明，HHT是一个潜在的替代治疗剂治疗肝癌。
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.
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