Bystander activity of Ad-mda7: human MDA-7 protein kills melanoma cells via an IL-20 receptor-dependent but STAT3-independent mechanism

Mol Ther. 2004 Dec;10(6):1085-95. doi: 10.1016/j.ymthe.2004.08.020.


The melanoma differentiation-associated gene-7 (mda-7/IL24) is a unique member of the IL-10 family of cytokines, with ubiquitous tumor cell proapoptotic activity. Transduction of tumor or normal cells with the mda-7 gene results in secretion of glycosylated MDA-7 protein. Recent data indicate that secreted MDA-7 protein functions as a pro-Th1 cytokine and as a potent antiangiogenic molecule. MDA-7 protein binds two distinct type II cytokine heterodimeric receptor complexes, IL-20R1/IL-20R2 (type 1 IL-20R) and IL-22R1/IL-20R2 (type 2 IL-20R). In this study we analyzed the activity of glycosylated secreted MDA-7 against human melanoma cells. MDA-7 protein induces phosphorylation and nuclear translocation of STAT3 in melanoma cells via both type 1 and type 2 IL-20R. MDA-7 induces dose-dependent cell death in melanoma tumor cells. MDA-7 receptor engagement results in up-regulation of BAX and subsequent apoptosis induction; this effect is mediated by STAT3-independent signaling. Additional IL-10 family members (IL-10, -19, -20, and -22) also activate STAT3; however, these ligands do not activate death pathways in melanoma. In normal cells, MDA-7 can bind to its cognate receptors and induce phosphorylation of STAT3, without cytotoxic sequelae. This study defines a tumor-selective cytotoxic bystander role for secreted MDA-7 protein and identifies a novel receptor-mediated, STAT3-independent, and PKR-independent death pathway.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Active Transport, Cell Nucleus
  • Adenoviridae / genetics*
  • Apoptosis / genetics*
  • Bystander Effect / physiology*
  • Cell Cycle
  • Cell Line, Tumor
  • DNA-Binding Proteins / metabolism*
  • Genes, Tumor Suppressor
  • Humans
  • Interleukin-10 / classification
  • Interleukin-10 / pharmacology
  • Interleukins / chemistry
  • Interleukins / genetics
  • Interleukins / metabolism*
  • Melanoma / metabolism
  • Melanoma / pathology*
  • Phosphorylation
  • Receptors, Interleukin / metabolism*
  • STAT3 Transcription Factor
  • Trans-Activators / metabolism*
  • eIF-2 Kinase / metabolism


  • DNA-Binding Proteins
  • Interleukins
  • Receptors, Interleukin
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Trans-Activators
  • interleukin-20 receptor
  • interleukin-24
  • Interleukin-10
  • eIF-2 Kinase