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S6K1 inhibition enhances tamoxifen-induced cell death in MCF-7 cells through translational inhibition of Mcl-1 and survivin

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Abstract

S6 kinase 1 (S6K1) was suggested to be a marker for endocrine therapy resistance in breast cancer. We examined whether tamoxifen’s effect can be modulated by S6K1 inhibition. S6K1 inhibition by PF4708671, a selective inhibitor of S6K1, acts synergistically with tamoxifen in S6K1-high MCF-7 cells. Similarly, the knockdown of S6K1 with small interfering RNA (siRNA) significantly sensitized MCF-7 cells to tamoxifen. Inhibition of S6K1 by PF4708671 led to a marked decrease in the expression levels of the anti-apoptotic proteins Mcl-1 and survivin, which was not related to mRNA levels. In addition, suppression of Mcl-1 or survivin, using specific siRNA, further enhanced cell sensitivity to tamoxifen. These results showed that inhibition of S6K1 acts synergistically with tamoxifen, via translational modulation of Mcl-1 and survivin. Based on these findings, we propose that targeting S6K1 may be an effective strategy to overcome tamoxifen resistance in breast cancer.

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Abbreviations

ER:

Estrogen receptor

mTOR:

Mammalian target of rapamycin

S6K1:

Ribosomal p70 S6 kinase

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Acknowledgments

This research has been supported by a grant from the Radiological Translational Research Program (50451-2013).

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Correspondence to Woo Chul Noh.

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Sung-Eun Hong, Eun-Kyu Kim and Hyeon-Ok Jin contributed equally to this study.

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Hong, SE., Kim, EK., Jin, HO. et al. S6K1 inhibition enhances tamoxifen-induced cell death in MCF-7 cells through translational inhibition of Mcl-1 and survivin. Cell Biol Toxicol 29, 273–282 (2013). https://doi.org/10.1007/s10565-013-9253-2

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  • DOI: https://doi.org/10.1007/s10565-013-9253-2

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