Induction of stem cell factor/c-Kit/slug signal transduction in multidrug-resistant malignant mesothelioma cells.
Malignant mesothelioma (MM) is strongly resistant to conventional chemotherapy by unclear mechanisms. We and others have previously reported that cytokine- and growth factor-mediated signal transduction is involved in the growth and progression of MM. Here, we identified a pathway that involves stem cell factor (SCF)/c-Kit/Slug in mediating multidrug resistance of MM cells. When we compared gene expression profiles between five MM cells and their multidrug-resistant (MM DX) sublines, we found that MM DX cells expressed both SCF and c-Kit and had higher mRNA levels of Slug. Knockdown of c-Kit or Slug expression with their respective small interfering RNA sensitized MM DX cells to the induction of apoptosis by different chemotherapeutic agents, including doxorubicin, paclitaxel, and vincristine. Transfection of c-Kit in parental MM cells in the presence of SCF up-regulated Slug and increased resistance to the chemotherapeutic agents. Moreover, MM cells expressing Slug showed a similar increased resistance to the chemotherapeutic agents. These results indicate that induction of Slug by autocrine production of SCF and c-Kit activation plays a key role in conferring a broad spectrum chemoresistance on MM cells and reveal a novel signal transduction pathway for pharmacological or genetic intervention of MM patients.
Catalano
Alfonso
A
Department of Molecular Pathology and Innovative Therapies, Polytechnic University of Marche, Ancona 60131, Italy. catgfp@yahoo.it
Rodilossi
Sabrina
S
Rippo
Maria Rita
MR
Caprari
Paola
P
Procopio
Antonio
A
D017209:Apoptosis; D045744:Cell Line, Tumor; D002469:Cell Separation; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis; D018076:DNA, Complementary / Q000378:metabolism; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D008654:Mesothelioma / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology; D010641:Phenotype; D010957:Plasmids / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D019089:Stem Cell Factor / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation; D014700:Verapamil / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology
D017077:Culture Media, Conditioned; D016207:Cytokines; D018076:DNA, Complementary; D034741:RNA, Small Interfering; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D019089:Stem Cell Factor; D014157:Transcription Factors; D014750:Vincristine; D004317:Doxorubicin; D014700:Verapamil; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D017239:Paclitaxel