Analysis of molecular target(s) of naringenin in MCF-7 breast cancer cells

UNCG Author/Contributor (non-UNCG co-authors, if there are any, appear on document)
Lauren A. Eanes (Creator)
The University of North Carolina at Greensboro (UNCG )
Web Site:
Yashomati Patel

Abstract: Estrogen receptor (ER) antagonists such as tamoxifen have been used successfully to treat ER+ breast cancers for more than 30 years. Tamoxifen targets the ER and blocks the binding of estrogen thus preventing up-regulation of estrogen responsive genes and resulting in impaired cell proliferation. Unfortunately, long term use of tamoxifen can result in resistance. Previous studies have reported that naringenin, a flavanone, can inhibit cell proliferation and promote cell death in ER+ breast cancer cells. It has been reported that signaling pathways, such as mitogen activated protein kinase (MAPK), are up-regulated in tamoxifen resistant cells. Previous research suggests that naringenin inhibits the MAPK signaling pathways. For this study, I investigated the molecular targets of naringenin in tamoxifen-resistant cells in order to determine the mechanism of action of naringenin in impairing cell proliferation and survival to gain further insight in the mechanism of naringenin action and its use as a possible therapeutic treatment. To determine if naringenin is targeting the MAPK pathway, tamoxifen resistant MCF-7 breast cancer cells were treated with naringenin or U0126 a MAPK kinase inhibitor. Our studies show that while both U0126 and naringenin impair cell proliferation and viability the combination of U0126 and naringenin resulted in greater inhibition of cell viability than either compound alone. It has been previously reported that naringenin can bind the ER. Our lab has also shown that naringenin inhibits ERá from entering the nucleus thus ERá displays a peri-nuclear localization pattern. Confocal microscopy revealed that in U0126 treated cells ERá displayed an even distribution across the cell as seen in tamoxifen resistant cells. This suggests that MAPK is not the only target of naringenin. Thus to identify other possible molecular targets of naringenin we screened phage display libraries. Our phage display studies identified several members of the E3 ubiquitin ligase family which are responsible for targeting proteins for ubiquitination thus degradation. E3 ligases are important for proper regulation of protein levels within the cell. Together, our results suggest that MAPK is not the only target of naringenin. Instead these results suggest that naringenin could be targeting a more global protein such as E3 ligases and altering their activities thus altering the levels of target proteins involved in cell proliferation and survival. E3 ligases have been targeted by therapeutics for possible treatments in cancer and naringenin could be an effective therapeutic to target these E3 ligases.

Additional Information

Language: English
Date: 2014
Breast Cancer, E3 uniquitin ligases, Estrogen Receptor alpha, MAPK, Naringenin, Tamoxifen Resistance
Breast $x Cancer $x Treatment
Drug resistance in cancer cells
Estrogen $x Receptors $x Pathophysiology
Mitogen-activated protein kinases

Email this document to