Expression of FAP-1 by human colon adenocarcinoma: implication for resistance against Fas-mediated apoptosis in cancer.
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.
Yao
H
H
Department of Oncology, Sun-Yat-Sen Memorial Hospital, Guangzhou, People's Republic of China.
Song
E
E
Chen
J
J
Hamar
P
P
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D053222:Fas Ligand Protein; D006801:Humans; D007124:Immunoenzyme Techniques; D007075:Immunoglobulin M; D020287:In Situ Nick-End Labeling; D008024:Ligands; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000502:physiology*; D010446:Peptide Fragments / Q000494:pharmacology; D054645:Protein Phosphatase 1; D054595:Protein Tyrosine Phosphatase, Non-Receptor Type 13; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000502:physiology*
D000911:Antibodies, Monoclonal; D002352:Carrier Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D007075:Immunoglobulin M; D008024:Ligands; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D019014:fas Receptor; D054645:Protein Phosphatase 1; C516742:PTPN13 protein, human; D054595:Protein Tyrosine Phosphatase, Non-Receptor Type 13; D017027:Protein Tyrosine Phosphatases