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Midkine silencing enhances the anti–prostate cancer stem cell activity of the flavone apigenin: cooperation on signaling pathways regulated by ERK, p38, PTEN, PARP, and NF-κB

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Summary

Prostate cancer (PCa) is the most common cancer in men worldwide. Midkine (MK) is overexpressed in PCa, as well as in tumor-initiating cells termed cancer stem cells (CSCs). Apigenin is a dietary flavone with considerable anti-tumor activities. In this study, we explored the possible therapeutic use of MK silencing, apigenin treatment, and a combination of both on human PCa and prostate cancer stem cells (PCSCs). CD44+CD133+ PC3 and CD44+ LNCaP CSCs were isolated from their parent cell lines. Both MK knockdown and apigenin treatment resulted in loss of cell viability in PCSCs, and these effects were significantly elevated when apigenin was applied with MK silencing. Combined treatment of CD44+CD133+ PC3 cells with apigenin and MK siRNA was also more effective in inducing apoptotic and non-apoptotic cell death when compared with individual applications. Treatment of CD44+ LNCaP cells with apigenin significantly decreased viability, although the combination treatment did not markedly alter the individual therapy. Molecular events underlying cell cycle arrest and inhibition of the survival, proliferation, and migration of CD44+CD133+ PC3 cells were found to be associated with upregulated p21, p27, Bax, Bid, caspase-3, and caspase-8 expression, as well as downregulated p-p38, p-ERK, NF-κB, and PARP. In addition, the combination of apigenin treatment and MK silencing showed better outcomes on the anticancer efficacy of docetaxel in CD44+CD133+ PC3 cells. In conclusion, MK-regulated events are different between PCSCs, and when combined with apigenin plus MK silencing, docetaxel treatment may be a valuable approach for the eradication of PCSCs.

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Acknowledgments

The authors would like to thank to Dr. Gulperi Oktem for the useful discussions and help. We thank to Rıza Serttaş and Talha Baykul for their technical assistance.

Funding

The work was supported by the Scientific and Technological Research Council of Turkey (TUBITAK grant number: 115S356).

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  1. Department of Medical Biology, School of Medicine, Trakya University, Balkan Campus, 22030, Edirne, Turkey

    Suat Erdogan, Kader Turkekul, Zeynep B. Doganlar & Oguzhan Doganlar

  2. Department of Biochemistry, School of Medicine, Trakya University, Balkan Campus, 22030 Edirne, Turkey

    Ilker Dibirdik

  3. Department of Histology and Embryology, School of Medicine, Istanbul Aydin University, Istanbul, Turkey

    Ayhan Bilir

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Erdogan, S., Turkekul, K., Dibirdik, I. et al. Midkine silencing enhances the anti–prostate cancer stem cell activity of the flavone apigenin: cooperation on signaling pathways regulated by ERK, p38, PTEN, PARP, and NF-κB. Invest New Drugs 38, 246–263 (2020). https://doi.org/10.1007/s10637-019-00774-8

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