J Cancer 2021; 12(12):3548-3557. doi:10.7150/jca.50292

Research Paper

Lenvatinib induces anticancer activity in gallbladder cancer by targeting AKT

Jianwen Ye1,2*, Lei Qi3*, Jialu Liang1,2*, Ke Zong1,2, Wentao Liu1,2, Renfeng Li1,2, Ruo Feng4✉, Wenlong Zhai1,2✉

1. Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.
2. Key Lab of Digestive Organ Transplantation of Henan Province, Open and Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Zhengzhou Key Laboratory of Hepatobiliary and Pancreatic Disease and Organ Transplantation, Zhengzhou, Henan 450052, P.R. China.
3. Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China.
4. Department of Histology and Embryology, Medical College of Zhengzhou University, Zhengzhou 450052, P.R. China.
*These authors contributed equally to this work.

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Citation:
Ye J, Qi L, Liang J, Zong K, Liu W, Li R, Feng R, Zhai W. Lenvatinib induces anticancer activity in gallbladder cancer by targeting AKT. J Cancer 2021; 12(12):3548-3557. doi:10.7150/jca.50292. Available from https://www.jcancer.org/v12p3548.htm

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Abstract

Gallbladder cancer (GBC) is characterized by poor prognosis, early metastasis, and high recurrence rates, which seriously threaten human health. The effect of lenvatinib, a widely used drug in anti-hepatocellular carcinoma in China, on GBC progress, as well as its underlying molecular mechanism, remains unclear. Therefore, the present study investigated the effect of lenvatinib on human GBC GBC-SD and NOZ cells and its underlying mechanisms. A series of experiments, including cell proliferation, clone formation, wound healing, and cell migration and invasion assays, as well as flow cytometry, were performed to investigate the anticancer effect of lenvatinib on GBC. Western blotting was used to detect alterations in protein expression of CKD2, CKD4, cyclin D1, caspase-9, matrix metalloproteinase (MMP)-2, cell migration-inducing protein (CEMIP) and phospho-AKT (p-AKT). In addition, the chemosensitivity of lenvatinib-treated GBC cells to gemcitabine (GEM) and whether the activation of phosphoinositide 3 kinase (PI3K)/AKT contributed to the chemoresistance were determined. Finally, the anticancer effect of lenvatinib in vivo was detected using a xenograft mouse model. These data showed that treatment with lenvatinib inhibited cell proliferation, colony formation ability, migration, induced apoptosis, regulated cell cycle and resulted in decreased resistance to GEM. Treatment with lenvatinib decreased the expression of MMP-2, CEMIP, CDK2, CDK4 and cyclin D1, and increased the expression of cleaved caspase-9, which was mediated by the inactivation of the PI3K/AKT pathway in vitro. In addition, lenvatinib inhibited autophagy in GBC-SD and NOZ cells. Besides, Lenvatinib suppressed GBC cell growth in vivo by targeting p-AKT. In combination, the present data indicated that lenvatinib plays a potential anticancer role in GBC by downregulating the expression of p-AKT.

Keywords: lenvatinib, gallbladder cancer, proliferation, apoptosis, migration, AKT