Inhibition of Stat3 increases doxorubicin sensitivity in a human metastatic breast cancer cell line.
Metastatic breast cancer is an incurable disease, often characterized by poor response to standard chemotherapy, which is mainly based on anthracyclines and taxanes. Thus, increasing tumor cell sensitivity to these agents is an attractive goal towards improving the clinical management of this disease. The present study investigates the effects of signal transducer and activator of transcription 3 (Stat3) inhibition on the response of the highly metastatic MDA-MB-231 human breast adenocarcinoma cell line to doxorubicin (DOX). Stat3 is a transcription factor often constitutively activated in breast tumors and cancer cell lines, and is thought to contribute to malignant transformation and progression by transactivation of a host of target genes involved in cell proliferation and survival, angiogenesis and invasiveness. Our results indicate that (a) untreated MDA-MB-231 cells express higher baseline levels of (activated) pTyr(705)Stat3, that are further upregulated following exposure to DOX, than the non-metastatic MCF-7 cell line; (b) inhibiting the Stat3 signaling pathway, by exposure to the tyrphostin AG490 (an inhibitor of the upstream activating Janus kinases), by transfection with a dominant-negative form of Stat3 or by treatment with satraplatin (a tetravalent platinum derivative that inhibits Stat3 activation), increases breast cancer cell response to the proapoptotic effect of DOX (to different extents). In addition, the latter two approaches have been shown to interfere with expression of one or more antiapoptotic proteins. Overall, these observations suggest that suppression of Stat3 signaling may provide a potential therapeutic approach to overcoming DOX resistance in metastatic breast cancer cells.
Gariboldi
Marzia B
MB
Department of Structural and Functional Biology, Section of Pharmacology, University of Insubria, Via A. da Giussano 12, 21052 Busto Arsizio, Italy.
Ravizza
Raffaella
R
Molteni
Roberta
R
Osella
Domenico
D
Gabano
Elisabetta
E
Monti
Elena
E
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014162:Transfection; D020032:Tyrphostins / Q000494:pharmacology*
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D050796:STAT3 Transcription Factor; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D004317:Doxorubicin; C081294:satraplatin; D011505:Protein-Tyrosine Kinases