1. Academic Validation
  2. Lactoferrin targeting INTL1 receptor inhibits hepatocellular carcinoma progression via apoptosis and cell cycle signaling pathways

Lactoferrin targeting INTL1 receptor inhibits hepatocellular carcinoma progression via apoptosis and cell cycle signaling pathways

  • Sci Rep. 2024 Dec 28;14(1):31210. doi: 10.1038/s41598-024-82514-4.
Abdulkadir Cidem 1 2 Gary Ro-Lin Chang 1 Chih-Ching Yen 3 Ming-Shan Chen 4 Shang-Hsun Yang 5 Chuan-Mu Chen 6 7 8
Affiliations

Affiliations

  • 1 Department of Life Sciences, College of Life Sciences, National Chung Hsing University, Kuo Kuang Rd., Taichung, 402, Taiwan.
  • 2 Department of Molecular Biology and Genetics, Erzurum Technical University, Erzurum, 25250, Turkey.
  • 3 Department of Internal Medicine, China Medical University Hospital, College of Health Care, China Medical University, Taichung, 404, Taiwan.
  • 4 Department of Anesthesiology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, 600, Taiwan.
  • 5 Department of Physiology, Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, 70101, Taiwan.
  • 6 Department of Life Sciences, College of Life Sciences, National Chung Hsing University, Kuo Kuang Rd., Taichung, 402, Taiwan. chchen1@dragon.nchu.edu.tw.
  • 7 The iEGG and Animal Biotechnology Center, and Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, 402, Taiwan. chchen1@dragon.nchu.edu.tw.
  • 8 Center for General Educational, National Quemoy University, Kinmen, 892, Taiwan. chchen1@dragon.nchu.edu.tw.
Abstract

Hepatocellular carcinoma (HCC) constitutes 90% of liver Cancer cases and ranks as the third leading cause of cancer-related mortality, necessitating urgent development of alternative therapies. Lactoferrin (LF), a natural iron-binding glycoprotein with reported Anticancer effects, is investigated for its potential in liver Cancer treatment, an area with limited existing studies. This study focuses on evaluating LF's anti-liver Cancer effects on HCC cells and assessing the preventive efficacy of oral LF administration in a murine model. Data showed that LF exerted anti-proliferative effects on HepG2, Hep3B, and SK-Hep1 cells while having no cytotoxicity on healthy liver cells (FL83B). Mechanistically, LF induces mitochondrial-mediated Apoptosis and G0/G1 cell cycle arrest in HepG2 cells, associated with increased phosphorylation of p38 MAPK and JNK for Apoptosis, and ERK phosphorylation for cell cycle arrest. Intelectin-1 (INTL1) is identified as the receptor facilitating LF endocytosis in HepG2 cells, and downregulation of INTL1 inhibits LF-induced signaling pathways. Notably, oral LF administration prevents HCC development in nude mice with orthotopic HepG2 cell injection. This study unveils the mechanistic basis of LF action in HepG2 cells, showcasing its potential in HCC prevention. Importantly, we report the novel identification of INTL1 as the LF receptor in HepG2 cells, providing valuable insights for future exploration of LF and its derivatives in liver Cancer therapy.

Keywords

Apoptosis; Cell cycle arrest; Hepatocellular carcinoma (HCC); Intelectin-1 (INTL1); Lactoferrin (LF); Mitogen-activated protein kinase (MAPK).

Figures
Products