JNK/SAPK mediates doxorubicin-induced differentiation and apoptosis in MCF-7 breast cancer cells.
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.
Kim
Jayoung
J
Urologic Laboratory, Department of Urology, Children's Hospital Boston, MA 02115, USA.
Freeman
Michael R
MR
D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000473:pathology*; D002453:Cell Cycle; D002454:Cell Differentiation / Q000502:physiology*; D004273:DNA, Neoplasm / Q000032:analysis; D004317:Doxorubicin / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis* / Q000494:pharmacology*; D010766:Phosphorylation
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004317:Doxorubicin; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases