Differential regulation of MMP7 in colon cancer cells resistant and sensitive to oxaliplatin-induced cell death.
BACKGROUND
We have previously shown that metalloproteinase 7 (MMP7) expression is increased during the acquisition of resistance to oxaliplatin in colon cancer cells. Now we have analyzed the implication of β-catenin and EGFR pathways in the up-regulation of MMP7 in the oxaliplatin-resistant human colon cancer cell lines RHT29 and RHCT116 p53-/-, derived from the HT29 and HCT116 p53-/- cells, respectively.


RESULTS
Oxaliplatin treatment increased EGFR expression and induced its activation in all the cell lines. However, β-catenin mRNA was only upregulated in the HT29 and RHT29 cells, with a marked increase in the nuclear/cytoplasmic β-catenin protein ratio in the oxaliplatin-resistant RHT29 cells. To determine the contribution of β-catenin and EGFR to the expression of MMP7 we performed siRNA experiments. β-catenin abrogation only prevented the induction of MMP7 by oxaliplatin in HT29 and RHT29 cells. Accordingly, viability of oxaliplatin-treated RHT29 cells under β-catenin silencing was decreased. On the other hand, EGFR siRNA induced contradictory effects, decreasing PEA3 and MMP7 expression in control and oxaliplatin-treated RHCT116 p53-/- cells but increasing basal- and oxaliplatin-induced PEA3 and MMP7 in the HT29 and RHT29 cells.


CONCLUSIONS
Oxaliplatin-induced MMP7 up-regulation is differentially achieved in colon cancer cell lines, as a result of EGFR and β-catenin cross-talk on MMP7 gene transcription. Taken together, our results point out the disparity of effects that β-catenin and EGFR blocking therapeutic strategies may exert on MMP7 expression depending on the cellular context and remark the importance of a better knowledge of MMP7 regulation to improve chemotherapy effectiveness in colon cancer.
Ametller
Elisabet
E
Department of Medical Oncology, Universitat de Barcelona, Spain.
García-Recio
Susana
S
Pastor-Arroyo
Eva-María
EM
Callejo
Gerard
G
Carbó
Neus
N
Gascón
Pedro
P
Almendro
Vanessa
V
D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D020783:Matrix Metalloproteinase 7 / Q000096:biosynthesis* / Q000235:genetics; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D034741:RNA, Small Interfering; D014157:Transcription Factors; D051176:beta Catenin; C065788:transcription factor PEA3; D000077150:Oxaliplatin; D066246:ErbB Receptors; D020783:Matrix Metalloproteinase 7