Berberine Suppresses Lung Metastasis of Cancer via Inhibiting Endothelial Transforming Growth Factor Beta Receptor 1

Wenjia Tian; Huifeng Hao; Ming Chu; Jingjing Gong; Wenzhe Li; Yuan Fang; Jindong Zhang; Cunzheng Zhang; Yonghui Huang; Fei Pei; Liping Duan

doi:10.3389/fphar.2022.917827

Berberine Suppresses Lung Metastasis of Cancer via Inhibiting Endothelial Transforming Growth Factor Beta Receptor 1

Front Pharmacol. 2022 Jun 16:13:917827. doi: 10.3389/fphar.2022.917827. eCollection 2022.

Authors

Wenjia Tian^{1

2}, Huifeng Hao³, Ming Chu⁴, Jingjing Gong⁵, Wenzhe Li⁶, Yuan Fang¹, Jindong Zhang¹, Cunzheng Zhang¹, Yonghui Huang¹, Fei Pei⁷, Liping Duan¹

Affiliations

¹ Department of Gastroenterology, Peking University Third Hospital, Beijing, China.
² Department of Gastroenterology, Peking University International Hospital, Beijing, China.
³ Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education Beijing), Department of Integration of Chinese and Western Medicine, Peking University Cancer Hospital and Institute, Beijing, China.
⁴ Department of Immunology, School of Basic Medical Sciences, Peking University, NHC Key Laboratory of Medical Immunology (Peking University), Beijing, China.
⁵ Institute of Systems Biomedicine, Peking University Health Science Center, Beijing, China.
⁶ State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China.
⁷ Department of Pathology, Peking University Third Hospital, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.

Abstract

This study investigated the effects of berberine (BBR) on pancreatic cancer (PC) lung metastasis and explored the underlying mechanisms, using a BALB/C-nu/nu nude mouse model injected with PC cells (AsPC-1). Intragastric administration of BBR dose-dependently improves survival of mice intravenously injected with AsPC-1 cells, and reduces lung metastasis. Especially, BBR significantly reduces lung infiltration of circulating tumor cells (CTCs) 24 h after AsPC-1 cells injection. In vitro, tumor cells (TCs) trigger endothelial barrier disruption and promote trans-endothelial migration of CFSE-labeled TCs. BBR treatment effectively ameliorates TC-induced endothelial disruption, an effect that is diminished by inhibiting transforming growth factor-β receptor 1 (TGFBR1). Blocking TGFBR1 blunts the anti-metastatic effect of BBR in vivo. Mechanistically, BBR binds to the intercellular portion of TGFBR1, suppresses its enzyme activities, and protects endothelial barrier disruption by TCs which express higher levels of TGF-β1. Hence, BBR might be a promising drug for reducing PC lung metastasis in clinical practice.

Keywords: TGFBR1; berberine; cancer cell; endothelial barrier; endothelial cell; metastasis; pancreatic cancer; trans-endothelial migration.