Midkine downregulation increases the efficacy of quercetin on prostate cancer stem cell survival and migration through PI3K/AKT and MAPK/ERK pathway
Küçük Resim Yok
Tarih
2018
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
Elsevier France-Editions Scientifiques Medicales Elsevier
Erişim Hakkı
info:eu-repo/semantics/closedAccess
Özet
Aims: To examine the functions of growth factor midkine (MK) and a flavonoid quercetin on survival, apoptosis and migration of prostate cancer (PCa) stem cells (CSCs). Main methods: CD44(+)/CD133(+) and CD44(+) stem cells were isolated from PC3 and LNCaP cells, respectively by magnetic-activated cell sorting system. 3D cell culture was used to evaluate the ability of quercetin, MK siRNA, and the combination of both to inhibit spheroid formation, apoptosis and cell cycle arrest. Image-based cytometer, RT-qPCR, Western blotting and transwell migration assays were performed. Key findings: Quercetin treatment for 24-72 h inhibited PC3 and CD44+/CD133+ stem cell proliferation in a time-and dose-dependent manner. Knockdown of endogenous MK expression significantly suppressed proliferation of CD44(+)/CD133(+) and CD44(+) cells as well as their parent cells. Co-administration of MK siRNA and quercetin reduced the cell survival, induced apoptosis and caused G1 phase cell cycle arrest more effectively than the individual therapy. Knockdown of MK significantly enhanced the inhibitory effect of quercetin on CD44(+)/CD133(+) migration and spheroid formation. In addition, the combined therapy inhibited the phosphorylation of PI3K, AKT and ERK1/2, and reduced the protein expression of p38, ABCG2 and NF-kappa B. Significance: Quercetin alone exhibited significant cytotoxic effects on CD44(+)/CD133(+). MK plays an important role in the proliferation of CD44(+)/CD133(+) and CD44(+) cells in particular, and quercetin and MK-silencing therapy may be an important strategy in targeting CSCs that play a role in relapse, migration and drug resistance.
Açıklama
Anahtar Kelimeler
Quercetin, Prostate Cancer Stem Cells, PC3, Lncap, Midkine, Migration, Breast-Cancer, In-Vitro, Signaling Pathway, Cycle Arrest, Expression, Inhibition, Apoptosis, Growth, Proliferation, Resistance
Kaynak
Biomedicine & Pharmacotherapy
WoS Q Değeri
Q1
Scopus Q Değeri
Q1
Cilt
107
