Cell-surface nucleolin acts as a central mediator for carcinogenic, anti-carcinogenic, and disease-related ligands
Hirota Fujiki1, Tatsuro Watanabe, Masami Suganuma
1Research Institute for Clinical Oncology, Saitama Cancer Center, Saitama, 362-0806, Japan, uv4h-fjk@asahi-net.or.jp.
Purpose:
Cell-surface nucleolin in human gastric cancer cell lines is a receptor for TNF-α-inducing protein (Tipα) of Helicobacter pylori. The binding complex of nucleolin and Tipα is internalized into the cells and then induces tumor progression of human gastric cancer. Surface nucleolin is also a receptor of human immunodeficiency virus-1, and the anti-HIV pseudopeptide (HB-19) showed anti-carcinogenic activity in vivo. Surface nucleolin has dual functions depending on the ligands: In order to understand the mechanisms of surface nucleolin, it is necessary to review surface nucleolin and its relation to carcinogenic ligands and anti-carcinogenic ligands. Other ligands can be grouped among disease-related ligands, which is an important new topic for the prevention of various ailments.
Results And Discussion:
This paper mainly deals with two ligands of surface nucleolin, Tipα and pseudopeptide HB-19. The binding complex of nucleolin and Tipα induces expression of TNF-α and chemokine genes and activates NF-κB in gastric cancer cells of humans and mice. However, when human gastric cancer cell line MKN-1 was transfected with nucleolin-targeted siRNA, the result was inhibition of cell migration and elongation induced by Tipα. The amount of surface nucleolin was reduced in membrane fraction of the nucleolin knockdown MKN-1 cells, but the amount of nucleolin in the cytosol or nuclear fractions of the cells did not change. The results indicate that surface nucleolin acts as a carcinogenic mediator for Tipα of H. pylori. In contrast, both the viral external envelop glycoprotein gp120 of HIV and the anti-HIV pseudopeptide HB-19 bind to surface nucleolin. Through this binding, treatment with HB-19 inhibited tumor development in human breast cancer cell line MDA-MB-231 and rhabdoid tumor cell line derived from Wilms's tumor in xenograft nude mouse models. The results show that surface nucleolin acts as an anti-carcinogenic mediator for HB-19.
Conclusion:
Based on these discrete functions of surface nucleolin, the binding complex of carcinogenic ligands and surface nucleolin seems to be competing with that of anti-carcinogenic ligands and surface nucleolin. Moreover, carcinogenic ligands derived from endogenous sources play a significant role in human cancer development, and the interaction of surface nucleolin with disease-related ligands will be a new research subject for the prevention and treatment of various ailments.
Insights
Surface nucleolin acts as a dual receptor, mediating cancer progression with Helicobacter pylori Tipα and inhibiting tumors with anti-HIV peptide HB-19. This highlights its role in both carcinogenesis and cancer prevention.
Area of Science:
- Cell biology
- Molecular oncology
- Immunology
Background:
- Cell-surface nucleolin functions as a receptor for various ligands.
- Its interactions are implicated in both disease progression and therapeutic responses.
Purpose of the Study:
- To review the dual roles of cell-surface nucleolin.
- To explore its interactions with carcinogenic and anti-carcinogenic ligands.
- To identify new research avenues for disease prevention.
Main Methods:
- Investigated the binding of Helicobacter pylori TNF-α-inducing protein (Tipα) and anti-HIV pseudopeptide (HB-19) to cell-surface nucleolin.
- Utilized nucleolin-targeted siRNA in human gastric cancer cell lines.
- Assessed tumor development in xenograft nude mouse models.
Main Results:
- Tipα binding to nucleolin promotes gastric cancer progression by activating NF-κB and gene expression.
- Nucleolin knockdown inhibited Tipα-induced cell migration and elongation.
- HB-19 binding to nucleolin demonstrated anti-carcinogenic effects, inhibiting tumor growth in vivo.
Conclusions:
- Cell-surface nucleolin acts as a carcinogenic mediator for Tipα and an anti-carcinogenic mediator for HB-19.
- Competition exists between carcinogenic and anti-carcinogenic ligand binding to nucleolin.
- Interactions with disease-related ligands present a novel research area for ailment prevention and treatment.
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