Abstract 966: Lenvatinib induces apoptosis and inhibits metastasis through downregulate Wnt/GSK3β/NF-κB in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a prevalent cancer type and also the leading cause of cancer death among Taiwanese. The current treatments for liver cancer include eradication, chemical, targeted and radiotherapy… etc. Unfortunately, radiation therapy is quite harmful to patients and results in hepatic injury. Other treatment methods can only prolong patient9s life for few months, and has considerable side effects; therefore, it is extremely important to find other more effective drugs for HCC. HCC patients with higher expression level of ASPM (abnormal spindle-like microcephaly associated) have significantly lower survival rate than those of patients with lower expression level. ASPM is the co-activator of Wnt, which can activate the Wnt/β-catenin signaling pathway to increase the performance of GSK3β (Glycogen synthase kinase 3 beta) and regulate angiogenesis. In addition, studies have also found that GSK3β can also activate the transcription factor NF-κB, causing a large number of downstream proteins upregulation and thus triggered tumor growth and metastasis. Recent studies suggested that sorafenib has ability to inhibit the activation of transcription factor NF-κB and the expression of its downstream related proteins. Lenvatinib is also a multi-kinase inhibitor and had been approved by FDA for HCC treatment, which is more effective and with fewer skin side effects than sorafenib. However, whether the anti-tumor efficacy of lenvatinib in HCC was associated with the regulation of Wnt/GSK3β/NF-κB in HCC is remaining unclear. We aim to investigate whether the effect of lenvatinib in HCC, such as apoptosis induction and tumor metastasis inhibition, were associated with the inactivation of Wnt/GSK3B/NF-κB. Our studies demonstrated that lenvatinib can induce cytotoxicity of human HCC Hep3B and Huh7 cells. Lenvatinib may induce apoptosis effect via activated extrinsic- and intrinsic-apoptosis related molecules, including cleaved caspase-3, -8 and -9. Lenvatinib also significantly inhibited metastasis through the reduction of NF-κB-mediated metastasis associated proteins expression (MMP-2, MMP-9 and VEGF) and inhibition of invasion/migration ability in HCC cells. In addition, the inhibition of ASPM, Wnt and GSK3β were found after lenvatinib treatment in both in vitro and in vivo models. NF-κB activation was also effectively suppressed by lenvatinib in cells and animal model. Tumor growth inhibition was also found in lenvatinib treatment group. In conclusion, lenvatinib induces apoptosis and suppresses metastasis was associated with Wnt/GSK3β/NF-κB inactivation. Citation Format: Tsu-Lan Chao, Zhao-Lin Tan, I-Tsang Chiang, Yuan Chiang, Fei-Ting Hsu. Lenvatinib induces apoptosis and inhibits metastasis through downregulate Wnt/GSK3β/NF-κB in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 966.