Chlorotoxin-Fc fusion inhibits release of MMP-2 from pancreatic cancer cells.

Abstract

Chlorotoxin (CTX) is a 36-amino acid peptide derived from Leiurus quinquestriatus (scorpion) venom, which inhibits low-conductance chloride channels in colonic epithelial cells. It has been reported that CTX also binds to matrix metalloproteinase-2 (MMP-2), membrane type-1 MMP, and tissue inhibitor of metalloproteinase-2, as well as CLC-3 chloride ion channels and other proteins. Pancreatic cancer cells require the activation of MMP-2 during invasion and migration. In this study, the fusion protein was generated by joining the CTX peptide to the amino terminus of the human IgG-Fc domain without a hinge domain, the monomeric form of chlorotoxin (M-CTX-Fc). The resulting fusion protein was then used to target pancreatic cancer cells (PANC-1) in vitro. M-CTX-Fc decreased MMP-2 release into the media of PANC-1 cells in a dose-dependent manner. M-CTX-Fc internalization into PANC-1 cells was observed. When the cells were treated with chlorpromazine (CPZ), the internalization of the fusion protein was reduced, implicating a clathrin-dependent internalization mechanism of M-CTX-Fc in PANC-1 cells. Furthermore, M-CTX-Fc clearly exhibited the inhibition of the migration depending on the concentration, but human IgG, as negative control of Fc, was not affected. The M-CTX-Fc may be an effective instrument for targeting pancreatic cancer.

• Authors: Samah El-Ghlban, Tomonari Kasai, Tsukasa Shigehiro, Hong Xia Yin, Sreeja Sekhar, Mikiko Ida, Anna Sanchez, Akifumi Mizutani, Takayuki Kudoh, Hiroshi Murakami, Masaharu Seno
• Journal: BioMed research international (Biomed Res Int) Vol. 2014 Pg. 152659 ( 2014) ISSN: 2314-6141 [Electronic] United States
• PMID: 24511528 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chloride Channels
• ClC-3 channel
• Immunoglobulin Fc Fragments
• Immunoglobulin G
• Recombinant Fusion Proteins
• Scorpion Venoms
• Chlorotoxin
• Matrix Metalloproteinase 2

Topics

• Cell Line, Tumor
• Chloride Channels (biosynthesis, genetics)
• Gene Expression Regulation, Neoplastic (genetics, immunology)
• Humans
• Immunoglobulin Fc Fragments (genetics, immunology)
• Immunoglobulin G (genetics, immunology)
• Matrix Metalloproteinase 2 (biosynthesis, drug effects)
• Pancreatic Neoplasms (drug therapy, genetics, pathology)
• Recombinant Fusion Proteins (genetics, immunology)
• Scorpion Venoms (administration & dosage, chemistry)