title: Fas/FasL-dependent and -independent activation of caspase-8 in doxorubicin-treated human breast cancer MCF-7 cells: ADAM10 down-regulation activates Fas/FasL signaling pathway.
abstract: The contribution of Fas-mediated death pathway to doxorubicin-induced death of MCF-7 cells is not unambiguously elucidated. Thus, this study was conducted to explore doxorubicin-induced Fas/FasL signaling pathway activation in MCF-7 cells and doxorubicin-resistant MCF-7 (MCF-7/Dox) cells. Doxorubicin-induced caspase-8 activation was found to be mediated through Akt/ERK inactivation and FasL-independent Fas pathway in MCF-7 cells, while caspase-8 activation in MCF-7/Dox cells depended exclusively on FasL-stimulated Fas pathway. Suppression of caspase-8 activation restored the viability of doxorubicin-treated MCF-7 cells and MCF-7/Dox cells. Contrary to FasL surface expression exclusively detected in MCF-7/Dox cells, intracellular FasL expression was noted with MCF-7 cells. Promotion of FasL translocation to the cell surface by lysophosphatidic acid evoked a FasL-activated Fas death pathway in MCF-7 cells. Doxorubixin-evoked β-TrCP up-regulation promoted Sp1 degradation, which subsequently suppressed ADAM10 expression in MCF-7 and MCF-7/Dox cells. Doxorubicin-induced down-regulation of ADAM10 reduced FasL shedding, leading to Fas pathway activation in MCF-7/Dox cells. Knock-down of ADAM10 induced death in MCF-7/Dox cells, but marginally reduced the viability of MCF-7 cells. Taken together, our data indicate that Akt/ERK-mediated caspase-8 activation and Fas/FasL-mediated caspase-8 activation mostly elucidate doxorubicin-induced death in MCF-7 cells and MCF-7/Dox cells, respectively. These observations suggest a promising therapeutic modality for overcoming doxorubicin-resistant breast cancer by targeting ADAM10 sheddase activity.
authors.affiliation: Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.
authors.forename: Wen-Hsin
authors.initials: WH
authors.lastname: Liu
authors.forename: Long-Sen
authors.initials: LS
authors.lastname: Chang
mesh_terms: D051722:ADAM Proteins / Q000235:genetics* / Q000378:metabolism; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics* / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D053222:Fas Ligand Protein / Q000378:metabolism*; D005260:Female; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D000903:Antibiotics, Antineoplastic; C491901:FAS protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008565:Membrane Proteins; D019014:fas Receptor; D004317:Doxorubicin; D053829:Amyloid Precursor Protein Secretases; D053181:Caspase 8; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human