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Inhibition of extracellular signal‐regulated kinase potentiates the apoptotic and antimetastatic effects of cyclin‐dependent kinase inhibitors on metastatic DU145 and PC3 prostate cancer cells
Author(s) -
Rencüzoğullari Özge,
Arısan Elif Damla,
Obakan Yerlikaya Pinar,
Çoker Gürkan Ajda,
Keskin Buse,
Palavan Ünsal Narçin
Publication year - 2019
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.27840
Subject(s) - du145 , protein kinase b , cyclin dependent kinase , kinase , mapk/erk pathway , microbiology and biotechnology , cancer research , biology , signal transduction , pi3k/akt/mtor pathway , apoptosis , cell growth , cancer cell , cell cycle , cancer , lncap , biochemistry , genetics
Abstract Purvalanol and roscovitine are specific cyclin‐dependent kinase (CDK) inhibitors, which have antiproliferative and apoptotic effects on various types of cancer. Although, the apoptotic accomplishment of purvalanol and roscovitine was elucidated at the molecular level, the underlying exact of drug‐induced apoptosis through mitogen‐activated protein kinase (MAPK) signaling still speculative. In addition, the role of CDK inhibitors in the downregulation of extracellular signal–regulated kinase 1/2 (ERK1/2)‐mediated epithelial‐mesenchymal transition (EMT) remains unclear. Here, we investigated the potential effect of each CDK inhibitors on cell proliferation, migration, and generation of reactive oxygen species due to the inhibition of MAPKs in metastatic DU145 and PC3 prostate cancer cells. We reported that purvalanol and roscovitine induced mitochondria membrane potential loss–dependent apoptotic cell death, which was also characterized by activation of several caspases, cleavage of poly (ADP‐ribose) polymerase‐1 in DU145 and PC3 cells. Cotreatment of either purvalanol or roscovitine with ERK1/2 inhibitor, U0126, synergistically suppressed cell proliferation, and induced apoptotic action. Also, ERK1/2 inhibition potentiated the effect of each CDK inhibitor on the downregulation of EMT processes via increasing the epithelial marker and decreasing mesenchymal markers through reduction of Wnt signaling regulators in DU145 cells. This study provides biological evidence about purvalanol and roscovitine have apoptotic and antimetastatic effects via MAPK signaling on prostate cancer cell by activation of GSK3β signaling and inhibition of phosphoinositide‐3‐kinase/AKT (PI3K/AKT) pathways involved in the EMT process.