1. The Role of MMP7 and its cross-talk with the FAS/FASL system during the acquisition of chemoresistance to oxaliplatin
- Author
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Ignasi Casas, Vanessa Almendro, Pedro Gascón, Joan Maurel, Olga Collazo, Susana García-Recio, Josep M. Augé, Elisabet Ametller, and Universitat de Barcelona
- Subjects
Cancer cells ,Organoplatinum Compounds ,Colorectal cancer ,lcsh:Medicine ,Apoptosis ,Drug resistance ,MMP7 ,Fas ligand ,Neoplasm ,lcsh:Science ,Càncer ,Cancer ,Multidisciplinary ,Cell Biology/Cellular Death and Stress Responses ,Up-Regulation ,Oxaliplatin ,Malalties del còlon ,Matrix Metalloproteinase 7 ,Colonic Neoplasms ,Cèl·lules canceroses ,HT29 Cells ,medicine.drug ,Research Article ,Fas Ligand Protein ,MAP Kinase Signaling System ,Colon ,Oncology/Gastrointestinal Cancers ,Biology ,Downregulation and upregulation ,Cell Line, Tumor ,medicine ,Humans ,fas Receptor ,Colonic diseases ,neoplasms ,Cell Biology/Gene Expression ,Resistència als medicaments ,lcsh:R ,Receptor Cross-Talk ,medicine.disease ,digestive system diseases ,Drug Resistance, Neoplasm ,Immunology ,Cancer research ,lcsh:Q ,Tumor Suppressor Protein p53 ,Còlon - Abstract
BACKGROUND: The efficacy of oxaliplatin in cancer chemotherapy is limited by the development of drug resistance. MMP7 has been related to the loss of tumor cell response to cytotoxic agents although the exact mechanism is not fully understood. Moreover, MMP7 is an independent prognosis factor for survival in patients with colorectal cancer. The aim of the present study was to analyze the role of MMP7 and its cross-talk with the Fas/FasL system during the acquisition of oxaliplatin resistance in colon cancer cells. PRINCIPAL FINDINGS: For this purpose we have developed three different oxaliplatin-resistant cell lines (RHT29, RHCT116 p53(+/+), RHCT116 p53(-/-)) from the parental HT29, HCT116 p53(+/+) and HCT116 p53(-/-) colon cancer cells. MMP7 basal expression was higher in the resistant compared to the parental cell lines. MMP7 was also upregulated by oxaliplatin in both HT29 (p53 mutant) and RHCT116 p53(-/-) but not in the RHCT116 p53(+/+). Inhibition of MMP by 1,10-phenantroline monohydrate or siRNA of MMP7 restores cell sensitivity to oxaliplatin-induced apoptosis in both HT29 and RHCT116 p53(-/-) but not in the RHCT116 p53(+/+). Some of these effects are caused by alterations in Fas receptor. Fas is upregulated by oxaliplatin in colon cancer cells, however the RHT29 cells treated with oxaliplatin showed a 3.8-fold lower Fas expression at the cell surface than the HT29 cells. Decrease of Fas at the plasma membrane seems to be caused by MMP7 since its inhibition restores Fas levels. Moreover, functional analysis of Fas demonstrates that this receptor was less potent in inducing apoptosis in RHT29 cells and that its activation induces MAPK signaling in resistant cells. CONCLUSIONS: Taking together, these results suggest that MMP7 is related to the acquisition of oxaliplatin-resistance and that its inhibition restores drug sensitivity by increasing Fas receptor. Furthermore, Fas undergoes a change in its functionality in oxaliplatin-resistant cells inducing survival pathways instead of apoptotic signals.