JNK/SAPK mediates doxorubicin-induced differentiation and apoptosis in MCF-7 breast cancer cells

Breast Cancer Res Treat. 2003 Jun;79(3):321-8. doi: 10.1023/a:1024043302583.

Abstract

Pharmacologic induction of cancer cell differentiation has potential in the treatment of breast cancer. Doxorubicin, a widely used anthracycline antibiotic, was previously reported to induce differentiation of MCF-7 breast cancer cells. We demonstrate in this study that inhibition of MCF-7 breast cancer cell growth by low dose doxorubicin (0.01 microg/ml) was accompanied by an increase in cytokeratin 8/18 and milk fat globule membrane protein expression, biomarkers for differentiation of breast cancer, as well as an increase in JNK/SAPK phosphorylation. High dose doxorubicin (10.0 microg/ml) induced apoptosis in these cells. Overexpression of dominant-inhibitory forms of JNK1 and c-Jun blocked both the differentiation and apoptotic effects of doxorubicin. These results suggest that JNK/SAPK pathway signaling plays a prominent role in doxorubicin-induced cell cycle withdrawal, differentiation and control of apoptosis in this cell system. These findings support the possibility that JNK/SAPK pathway activation may be a means of therapeutic intervention in breast cancer.

Publication types

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

MeSH terms

  • Antineoplastic Agents / pharmacokinetics*
  • Apoptosis / physiology*
  • Blotting, Western
  • Breast Neoplasms / pathology*
  • Cell Cycle
  • Cell Differentiation / physiology*
  • DNA, Neoplasm / analysis
  • Doxorubicin / pharmacology*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase 8
  • Mitogen-Activated Protein Kinases / biosynthesis*
  • Mitogen-Activated Protein Kinases / pharmacology*
  • Phosphorylation

Substances

  • Antineoplastic Agents
  • DNA, Neoplasm
  • Doxorubicin
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase 8
  • Mitogen-Activated Protein Kinases