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

  • Suat ErdoganEmail author
  • Kader Turkekul
  • Ilker Dibirdik
  • Zeynep B. Doganlar
  • Oguzhan Doganlar
  • Ayhan Bilir


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.


Apigenin Midkine Prostate cancer CD44 CD133 Cancer stem cell 



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.


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

Compliance with ethical standards

Conflict of interest

Suat Erdogan declares that he has no conflict of interest. Kader Turkekul declares that she has no conflict of interest. Ilker Dibirdik declares that he has no conflict of interest. Zeynep B. Doganlar declares that she has no conflict of interest. Oguzhan Doganlar declares that he has no conflict of interest. Ayhan Bilir declares that he has no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

For this type of study, formal consent is not required.

Supplementary material

10637_2019_774_MOESM1_ESM.pdf (218 kb)
ESM 1 (PDF 217 kb)


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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Medical Biology, School of MedicineTrakya UniversityEdirneTurkey
  2. 2.Department of Biochemistry, School of MedicineTrakya University22030 EdirneTurkey
  3. 3.Department of Histology and Embryology, School of MedicineIstanbul Aydin UniversityIstanbulTurkey

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