Suat Erdogan1, Zeynep B Doganlar2, Oguzhan Doganlar2, Kader Turkekul2, Riza Serttas2. 1. Department of Medical Biology, School of Medicine, Trakya University, Balkan Campus, Edirne, Turkey. Electronic address: suaterdogan@trakya.edu.tr. 2. Department of Medical Biology, School of Medicine, Trakya University, Balkan Campus, Edirne, Turkey.
Abstract
BACKGROUND: Midkine (MDK) is a tumor-promoting factor that is often overexpressed in various human carcinomas, and the role of MDK has not yet been fully investigated in prostate cancer stem cells. MATERIALS AND METHODS: Prostate cancer CD133+ stem cells (PCSCs) were isolated from human castration-resistant PC3 cells. PCSCs were treated with different concentrations of MDK inhibitor, iMDK, for 24-72 hours. The IC50 values were determined by the MTT test. Endogenous MDK messenger RNA expression was knocked down by small interfering RNA. Quantitative reverse transcription polymerase chain reaction, Western blot analyses and image-based cytometry were used to investigate apoptosis and cell cycle progression as well as their underlying molecular mechanisms. Cell migration was evaluated by the wound healing test. RESULTS: iMDK caused dose- and time-dependent inhibition of PCSC survival. Similar growth inhibition was also obtained by small interfering RNA-mediated knockdown of endogenous MDK expression. iMDK was shown to preferentially induce cell cycle arrest at the S and G2/M phases. Suppressed PCSC growth was also accompanied by increases in p53 and the cell cycle inhibitor p21 genes. Combinatorial treatment of iMDK with docetaxel significantly inhibited cell proliferation versus either of the agents used alone. Inhibition of MDK expression strongly suppressed the migration of PCSCs compared to untreated and docetaxel-treated cells. iMDK and the knockdown of MDK decreased p-Akt and significantly upregulated the expression of PI3K/phosphatase/tensin homolog. CONCLUSIONS: Our data indicate that MDK plays a crucial role in controlling PCSC proliferation and migration. Therefore, suppression of endogenous expression of MDK would, in combination with traditional chemotherapy drugs, be a potential treatment for PCSCs.
BACKGROUND:Midkine (MDK) is a tumor-promoting factor that is often overexpressed in various humancarcinomas, and the role of MDK has not yet been fully investigated in prostate cancer stem cells. MATERIALS AND METHODS:Prostate cancerCD133+ stem cells (PCSCs) were isolated from human castration-resistant PC3 cells. PCSCs were treated with different concentrations of MDK inhibitor, iMDK, for 24-72 hours. The IC50 values were determined by the MTT test. Endogenous MDK messenger RNA expression was knocked down by small interfering RNA. Quantitative reverse transcription polymerase chain reaction, Western blot analyses and image-based cytometry were used to investigate apoptosis and cell cycle progression as well as their underlying molecular mechanisms. Cell migration was evaluated by the wound healing test. RESULTS: iMDK caused dose- and time-dependent inhibition of PCSC survival. Similar growth inhibition was also obtained by small interfering RNA-mediated knockdown of endogenous MDK expression. iMDK was shown to preferentially induce cell cycle arrest at the S and G2/M phases. Suppressed PCSC growth was also accompanied by increases in p53 and the cell cycle inhibitor p21 genes. Combinatorial treatment of iMDK with docetaxel significantly inhibited cell proliferation versus either of the agents used alone. Inhibition of MDK expression strongly suppressed the migration of PCSCs compared to untreated and docetaxel-treated cells. iMDK and the knockdown of MDK decreased p-Akt and significantly upregulated the expression of PI3K/phosphatase/tensin homolog. CONCLUSIONS: Our data indicate that MDK plays a crucial role in controlling PCSC proliferation and migration. Therefore, suppression of endogenous expression of MDK would, in combination with traditional chemotherapy drugs, be a potential treatment for PCSCs.
Authors: Thomas Kryza; Nathalie Bock; Scott Lovell; Anja Rockstroh; Melanie L Lehman; Adam Lesner; Janaththani Panchadsaram; Lakmali Munasinghage Silva; Srilakshmi Srinivasan; Cameron E Snell; Elizabeth D Williams; Ladan Fazli; Martin Gleave; Jyotsna Batra; Colleen Nelson; Edward W Tate; Jonathan Harris; John D Hooper; Judith A Clements Journal: Mol Oncol Date: 2019-11-28 Impact factor: 6.603
Authors: Zachery R Reichert; Tadas Kasputis; Srinivas Nallandhighal; Sophia M Abusamra; Amy Kasputis; Saloni Haruray; Yugang Wang; Shamara Williams; Udit Singhal; Ajjai Alva; Frank C Cackowski; Megan E V Caram; Phillip L Palmbos; Sarah E Yentz; David C Smith; Joshi J Alumkal; Todd M Morgan Journal: Int J Mol Sci Date: 2021-12-21 Impact factor: 6.208
Authors: Mikiko Nagashima; Travis S D'Cruz; Antoinette E Danku; Doneen Hesse; Christopher Sifuentes; Pamela A Raymond; Peter F Hitchcock Journal: J Neurosci Date: 2019-12-27 Impact factor: 6.167