Conflict of Interest Statement: The authors report no conflicts of interest.
Article first published online: 11 JUN 2013
Copyright © 2013 Wiley Periodicals, Inc.
Journal of Cellular Biochemistry
Volume 114, Issue 8, pages 1890–1900, August 2013
How to Cite
Shi, R., Peng, H., Yuan, X., Zhang, X., Zhang, Y., Fan, D., Liu, X. and Xiong, D. (2013), Down-regulation of c-fos by shRNA sensitizes adriamycin-resistant MCF-7/ADR cells to chemotherapeutic agents via P-glycoprotein inhibition and apoptosis augmentation. J. Cell. Biochem., 114: 1890–1900. doi: 10.1002/jcb.24533
Ruizan Shi and Hongwei Peng contributed equally to this work.
- Issue published online: 11 JUN 2013
- Article first published online: 11 JUN 2013
- Accepted manuscript online: 13 MAR 2013 09:13AM EST
- Manuscript Accepted: 27 FEB 2013
- Manuscript Received: 11 OCT 2012
- National Natural Science Foundation of China. Grant Numbers: 30873091, 30971291
- MULTIDRUG RESISTANCE (MDR);
- P-GLYCOPROTEIN (P-gp);
- APOPTOSIS RESISTANCE;
- MOLECULAR TARGET
Multidrug resistance (MDR) is a major hurdle in the treatment of cancer. Research indicated that the main mechanisms of most cancers included so-called “pump” (P-glycoprotein, P-gp) and “non-pump” (apoptosis) resistance. Identification of novel signaling molecules associated with both P-gp and apoptosis will facilitate the development of more effective strategies to overcome MDR in tumor cells. Since the proto-oncogene c-fos has been implicated in cell adaptation to environmental changes, we analyzed its role in mediating “pump” and “non-pump” resistance in MCF-7/ADR, an adriamycin (ADR)-selected human breast cancer cell line with the MDR phenotype. Elevated expression of c-fos in MCF-7/ADR cells and induction of c-fos by ADR in the parental drug-sensitive MCF-7 cells suggested a link between c-fos and MDR phenotype. Down-regulation of c-fos expression via shRNA resulted in sensitization of MCF-7/ADR cells to chemotherapeutic agents, including both P-gp and non-P-gp substrates. Further results proved that c-fos down-regulation in MCF-7/ADR cells resulted in decreased P-gp expression and activity, enhanced apoptosis, and altered expression of apoptosis-associated proteins (i.e., Bax, Bcl-2, p53, and PUMA). All above facts indicate that c-fos is involved in both P-gp- and anti-apoptosis-mediated MDR of MCF-7/ADR cells. Based on these results, we propose that c-fos may represent a potential molecular target for resistant cancer therapy, and suppressing c-fos gene expression may therefore be an effective means to temper breast cancer cell's MDR to cytotoxic chemotherapy. J. Cell. Biochem. 114: 1890–1900, 2013. © 2013 Wiley Periodicals, Inc.