Thymoquinone inhibits cell proliferation, migration, and invasion by regulating the elongation factor 2 kinase (eEF-2K) signaling axis in triple-negative breast cancer

Abstract

Background/purpose

Triple-negative breast cancer (TNBC) is the most aggressive and chemoresistant subtype of breast cancer. Therefore, new molecular targets and treatments need to be developed to improve poor patient prognosis and survival. We have previously shown that eukaryotic elongation factor 2 kinase (eEF-2K) is highly expressed in TNBC cells, is associated with poor patient survival and prognosis, and promotes cell proliferation, migration, and invasion. In vivo targeting of eEF-2K significantly reduces the tumor growth of orthotopic TNBC xenograft mouse models, suggesting that eEF-2K may serve as a potential novel therapeutic target.

Methods/results

In the current study, we identified thymoquinone (TQ), an active ingredient of Nigella sativa, as a potential safe and effective eEF-2K inhibitor in TNBC. We demonstrated for the first time that TQ inhibits the protein and mRNA expression of eEF-2K, as well as the clinically relevant downstream targets, including Src/FAK and Akt, and induces the tumor suppressor miR-603, in response to NF-kB inhibition. This effect was associated with a significant decrease in the proliferation, colony formation, migration, and invasion of TNBC cells. Furthermore, systemic in vivo injection of TQ (20 and 100 mg/kg) significantly reduced the growth of MDA-MB-231 tumors and inhibited the eEF-2K expression in an orthotopic tumor model in mice.

Conclusion

Our study provides first evidence that TQ treatment inhibits cell proliferation, migration/invasion, and tumor growth, in part through the inhibition of eEF-2K signaling in TNBC. Thus, our findings suggest that systemic TQ treatment may be used as a targeted therapeutic strategy for the inhibition of eEF-2K in TNBC tumor growth and progression.

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Acknowledgements

N.N.K. and B.O. conceived and coordinated the study and wrote the paper. N.N.K. performed in vitro experiments. R.B. assisted in experimental design and performed the overexpression of genes and assisted in the preparation of the figures. B.O. and N.K. prepared nanoliposomal particles incorporating TQ and performed in vivo studies. H.A.M. provided technical assistance for the animal study. G.C. and G.L.B. contributed to writing the manuscript. All authors analyzed the results and approved the final version of the manuscript.

Funding

This study was supported by the funding from Non-Coding RNA Center at M.D. Anderson Cancer Center and U54 NIH/NCI.

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Correspondence to Bulent Ozpolat.

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Kabil, N., Bayraktar, R., Kahraman, N. et al. Thymoquinone inhibits cell proliferation, migration, and invasion by regulating the elongation factor 2 kinase (eEF-2K) signaling axis in triple-negative breast cancer. Breast Cancer Res Treat 171, 593–605 (2018). https://doi.org/10.1007/s10549-018-4847-2

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Keywords

  • Thymoquinone
  • eEF-2K
  • MiR-603
  • Triple-negative breast cancer