Expression of FAP-1 by human colon adenocarcinoma: implication for resistance against Fas-mediated apoptosis in cancer.

Abstract

Although colon carcinoma cells express Fas receptors, they are resistant to Fas-mediated apoptosis. Defects within the intracellular Fas signal transduction may be responsible. We investigated whether the Fas-associated phosphatase-1 (FAP-1), an inhibitor of Fas signal transduction, contributed to this resistance in colon carcinomas. In vivo, apoptosis of cancer cells was detected in situ using terminal deoxynucleotidyltransferase-mediated dUTP nick-end labelling (TUNEL). FAP-1, FasR, and Fas ligand (FasL) were detected using immunohistochemistry. In vitro, colon carcinoma cells were primarily cultured, and their sensitivity to Fas-mediated apoptosis was evaluated by treatment with agonistic anti-FasR CH11 IgM monoclonal antibody in the presence or absence of synthetic Ac-SLV (serine-leucine-valine) tripeptide. Fas-associated phosphatase-1 expression was detected in 20 out of 28 colon adenocarcinomas. In vivo, a positive correlation between the percentage of apoptotic tumour cells and the number of FasL-positive tumour infiltrating lymphocytes was observed in FAP-1 negative cancers, but not in FAP-1-positive ones. Primarily cultured colon cancer cells, which were refractory to CH-11-induced apoptosis, had higher expression of FAP-1 on protein and mRNA levels than the sensitive group. Resistance to Fas-mediated apoptosis in tumour cells could be abolished by Ac-SLV tripetides. Fas-associated phosphatase-1 expression protects colon cancer cells from Fas-mediated apoptosis, and blockade of FAP-1 and FasR interaction sensitises tumour cells to Fas-dependent apoptosis.

• Authors: H Yao, E Song, J Chen, P Hamar
• Journal: British journal of cancer (Br J Cancer) Vol. 91 Issue 9 Pg. 1718-25 (Nov 01 2004) ISSN: 0007-0920 [Print] England
• PMID: 15494722 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Carrier Proteins
• FASLG protein, human
• Fas Ligand Protein
• Immunoglobulin M
• Ligands
• Membrane Glycoproteins
• Peptide Fragments
• RNA, Messenger
• RNA, Neoplasm
• fas Receptor
• Protein Phosphatase 1
• PTPN13 protein, human
• Protein Tyrosine Phosphatase, Non-Receptor Type 13
• Protein Tyrosine Phosphatases

Topics

• Adenocarcinoma (metabolism, pathology)
• Antibodies, Monoclonal (pharmacology)
• Apoptosis
• Carrier Proteins (genetics, metabolism)
• Colonic Neoplasms (metabolism, pathology)
• Fas Ligand Protein
• Humans
• Immunoenzyme Techniques
• Immunoglobulin M
• In Situ Nick-End Labeling
• Ligands
• Lymphocytes, Tumor-Infiltrating (immunology, pathology)
• Membrane Glycoproteins (physiology)
• Peptide Fragments (pharmacology)
• Protein Phosphatase 1
• Protein Tyrosine Phosphatase, Non-Receptor Type 13
• Protein Tyrosine Phosphatases (genetics, metabolism)
• RNA, Messenger (genetics, metabolism)
• RNA, Neoplasm (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Tumor Cells, Cultured
• fas Receptor (physiology)