Tumor promoting effects of CD95 signaling in chemoresistant cells.
BACKGROUND
CD95 is a death receptor controlling not only apoptotic pathways but also activating mechanisms promoting tumor growth. During the acquisition of chemoresistance to oxaliplatin there is a progressive loss of CD95 expression in colon cancer cells and a decreased ability of this receptor to induce cell death. The aim of this study was to characterize some key cellular responses controlled by CD95 signaling in oxaliplatin-resistant colon cancer cells.


RESULTS
We show that CD95 triggering results in an increased metastatic ability in resistant cells. Moreover, oxaliplatin treatment itself stimulates cell migration and decreases cell adhesion through CD95 activation, since CD95 expression inhibition by siRNA blocks the promigratory effects of oxaliplatin. These promigratory effects are related to the epithelia-to-mesenchymal transition (EMT) phenomenon, as evidenced by the up-regulation of some transcription factors and mesenchymal markers both in vitro and in vivo.


CONCLUSIONS
We conclude that oxaliplatin treatment in cells that have acquired resistance to oxaliplatin-induced apoptosis results in tumor-promoting effects through the activation of CD95 signaling and by inducing EMT, all these events jointly contributing to a metastatic phenotype.
Ametller
Elisabet
E
Medical Oncology, Institut d'Investigacions Biomèdiques Agustí Pi y Sunyer (IDIBAPS), Institut Clínic de Malalties Hemato-Oncològiques (ICMHO), Hospital Clínic, Facultat de Medicina, Universitat de Barcelona, Spain.
García-Recio
Susana
S
Costamagna
Domizziana
D
Mayordomo
Cristina
C
Fernández-Nogueira
Patricia
P
Carbó
Neus
N
Pastor-Arroyo
Eva María
EM
Gascón
Pedro
P
Almendro
Vanessa
V
D000970:Antineoplastic Agents / Q000494:pharmacology; D001483:Base Sequence; D015153:Blotting, Western; D002453:Cell Cycle; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering; D015398:Signal Transduction; D019014:fas Receptor / Q000378:metabolism*
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D034741:RNA, Small Interfering; D019014:fas Receptor; D000077150:Oxaliplatin