The novel FAT4 activator jujuboside A suppresses NSCLC tumorigenesis by activating HIPPO signaling and inhibiting YAP nuclear translocation.

Abstract

FAT atypical cadherin 4 (FAT4) has been identified as a tumor suppressor in lung cancers. However, no agent for lung cancer treatment targeting FAT4 has been used in the clinic. Jujuboside A (JUA) is a major active compound in Semen Ziziphi Spinosae. Semen Ziziphi Spinosae is a traditional Chinese herbal medicine used clinically for tumor treatment to improve patients' quality of life. However, the anti-lung cancer activity and the underlying mechanisms of JUA are not yet fully understood. Here, we demonstrated the anti-lung cancer activity of JUA in two lung cancer mice models and three non-small cell lung cancer (NSCLC) cell lines, and further illustrated its underlying mechanisms. JUA suppressed the occurrence and development of lung cancer and extended mice survival in vivo, and suppressed NSCLC cell activities through cell cycle arrest, proliferation suppression, stemness inhibition and senescence promotion. Moreover, JUA directly bound with and activated FAT4, subsequently activating FAT4-HIPPO signaling and inhibiting YAP nuclear translocation. Knockdown of FAT4 diminished JUA's effects on HIPPO signaling, YAP nuclear translocation, cell proliferation and cellular senescence. In conclusion, JUA significantly suppressed NSCLC tumorigenesis by regulating FAT4-HIPPO-YAP signaling. Our findings suggest that JUA is a novel FAT4 activator that can be developed as a promising NSCLC therapeutic agent targeting the FAT4-HIPPO-YAP pathway.

• Authors: Wensheng Wang, Qiuju Huang, Yao Chen, Zhiying Huang, Yanfang Huang, Ying Wang, Xiaoxiao Qi, Zhongqiu Liu, Linlin Lu
• Journal: Pharmacological research (Pharmacol Res) Vol. 170 Pg. 105723 (08 2021) ISSN: 1096-1186 [Electronic] Netherlands
• PMID: 34116210 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents, Phytogenic
• Cadherins
• FAT4 protein, human
• Saponins
• Tumor Suppressor Proteins
• YAP-Signaling Proteins
• YAP1 protein, human
• jujuboside A

Topics

• Active Transport, Cell Nucleus
• Animals
• Antineoplastic Agents, Phytogenic (pharmacology)
• Cadherins (agonists, metabolism)
• Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism, pathology)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cellular Senescence (drug effects)
• Hippo Signaling Pathway (drug effects)
• Humans
• Lung Neoplasms (drug therapy, metabolism, pathology)
• Mice
• Saponins (pharmacology)
• Tumor Suppressor Proteins (agonists, metabolism)
• YAP-Signaling Proteins (metabolism)