2. Academic Validation
  3. Activating the Hippo pathway by nevadensin overcomes Yap-drived resistance to sorafenib in hepatocellular carcinoma

Activating the Hippo pathway by nevadensin overcomes Yap-drived resistance to sorafenib in hepatocellular carcinoma

  • Discov Oncol. 2023 May 27;14(1):83. doi: 10.1007/s12672-023-00699-y.
Hewen Shi 1,  Ying Zou 1,  Xiaoxue Wang 1,  Guoli Wang 1,  Yijia Gao 2,  Fan Yi 2,  Junqing Xu 3,  Yancun Yin 4,  Defang Li 5,  Minjing Li 6
Affiliations

Affiliations

  • 1 Featured Laboratory for Biosynthesis and Target Discovery of Active Components of Traditional Chinese Medicine, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, Shandong, People's Republic of China.
  • 2 School of Basic Medical Sciences, Binzhou Medical University, Yantai, Shandong, People's Republic of China.
  • 3 Department of Hematology, Qingdao University Medical College, Affiliated Yantai Yuhuangding Hoepital, Yantai, Shandong, People's Republic of China.
  • 4 School of Basic Medical Sciences, Binzhou Medical University, Yantai, Shandong, People's Republic of China. [email protected].
  • 5 Featured Laboratory for Biosynthesis and Target Discovery of Active Components of Traditional Chinese Medicine, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, Shandong, People's Republic of China. [email protected].
  • 6 Featured Laboratory for Biosynthesis and Target Discovery of Active Components of Traditional Chinese Medicine, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, Shandong, People's Republic of China. [email protected].
PMID: 37243813 DOI: 10.1007/s12672-023-00699-y
Abstract

Background: Hepatocellular carcinoma (HCC) is a highly malignant type of tumor that is insensitive to cytotoxic chemotherapy and often develops drug resistance. Nevadensin, a bioflavonoid, exhibits anti-cancer properties in some cancers. However, the precise underlying mechanism of nevadensin against liver Cancer are poorly understood. We aim to evaluate the efficacy as well as the molecular mechanism of nevadensin in the treatment of liver Cancer.

Methods: Effects of nevadensin on HCC cell proliferation and Apoptosis were detected using EdU labeling and flow cytometry assays. The molecular mechanism of nevadensin on HCC was determined using RNAseq. The effects of nevadensin on hippo-Yap signaling were verified using western blot and RT-PCR.

Results: In this study, we show that nevadensin significantly inhibits growth of HCC cells via inducing cell cycle arrest and Apoptosis. RNAseq analysis showed that nevadensin regulates multiple functional signaling pathways associated with Cancer including Hippo signaling. Western Blot analysis revealed that nevadensin notably induces activation of the MST1/2- LATS1/2 kinase in HCC cells, further resulting in the primary effector molecule YAP phosphorylation and subsequent degradation. These results indicated that nevadensin might exert its anti-HCC activity through the Hippo-ON mechanism. Moreover, nevadensin could increase the sensitivity of HCC cells to sorafenib by down-regulating YAP and its downstream targets.

Conclusions: The present study indicates that nevadensin could be a potential effective approach to treating HCC, and overcoming sorafeni resistance via inducing activation of Hippo signaling.

Keywords

Hippo pathway; Nevadensin; Sensitization; YAP.

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