Induction of stem cell factor/c-Kit/slug signal transduction in multidrug-resistant malignant mesothelioma cells

J Biol Chem. 2004 Nov 5;279(45):46706-14. doi: 10.1074/jbc.M406696200. Epub 2004 Aug 26.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Cell Line, Tumor
  • Cell Separation
  • Culture Media, Conditioned / pharmacology
  • Cytokines / biosynthesis
  • DNA, Complementary / metabolism
  • Disease Progression
  • Dose-Response Relationship, Drug
  • Down-Regulation
  • Doxorubicin / pharmacology
  • Drug Resistance, Multiple*
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunoblotting
  • Immunoprecipitation
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / pathology*
  • Mesothelioma / drug therapy*
  • Mesothelioma / pathology
  • Paclitaxel / pharmacology
  • Phenotype
  • Plasmids / metabolism
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins c-kit / metabolism*
  • RNA, Small Interfering / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction*
  • Snail Family Transcription Factors
  • Stem Cell Factor / metabolism*
  • Transcription Factors / metabolism*
  • Transfection
  • Up-Regulation
  • Verapamil / pharmacology
  • Vincristine / pharmacology

Substances

  • Culture Media, Conditioned
  • Cytokines
  • DNA, Complementary
  • RNA, Small Interfering
  • SNAI1 protein, human
  • Snail Family Transcription Factors
  • Stem Cell Factor
  • Transcription Factors
  • Vincristine
  • Doxorubicin
  • Verapamil
  • Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins c-kit
  • Paclitaxel