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

Rencuzogullari O., Arisan E. D. , YERLİKAYA P. O. , ÇOKER GÜRKAN A., Keskin B., Unsal N. P.

JOURNAL OF CELLULAR BIOCHEMISTRY, vol.120, no.4, pp.5558-5569, 2019 (Peer-Reviewed Journal) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 120 Issue: 4
  • Publication Date: 2019
  • Doi Number: 10.1002/jcb.27840
  • Journal Indexes: Science Citation Index Expanded, Scopus
  • Page Numbers: pp.5558-5569
  • Keywords: apoptosis, epithelial-mesenchymal transition (EMT), extracellular signal-regulated kinase 1/2 (ERK1/2), purvalanol, roscovitine, EPITHELIAL-MESENCHYMAL TRANSITION, P38 MAPK, PATHWAY, ROSCOVITINE, ACTIVATION, PHOSPHORYLATION, PURVALANOL, CYC202, ERK1/2, U0126


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 GSK3 beta signaling and inhibition of phosphoinositide-3-kinase/AKT (PI3K/AKT) pathways involved in the EMT process.