Inhibition of didscoidin domain receptor 1 reduces epithelial–mesenchymal transition and induce cell‐cycle arrest and apoptosis in prostate cancer cell lines. Issue 11 (8th April 2019)

• Record Type: Journal Article
• Authors: Azizi, Reza; Salemi, Zahra; Fallahian, Faranak; Aghaei, Mahmoud
• Is Part Of: Journal of cellular physiology. Volume 234:Issue 11(2019:Nov.)
• Page Start: 19539
• Page End: 19552
• Publication Date: 2019-04-08
• Subjects: apoptosis -- cell‐cycle arrest -- discoidin domain receptor 1 (DDR1) -- EMT; Physiology -- Periodicals; Cell physiology -- Periodicals; 571.6
• DOI: 10.1002/jcp.28552
• Languages: English
• ISSNs: 0021-9541

Abstract

Abstract: Didscoidin domain receptor 1 (DDR1) is involved in the progression of prostate cancer metastasis through stimulation of epithelial–mesenchymal transition (EMT). So DDR1 inhibition can be a helpful target for cancer metastasis prevention. So, we studied the effects of DDR1 inhibition on EMT as well as induction of cell‐cycle arrest and apoptosis in prostate cancer cell lines. DDR1 expression was evaluated using reverse‐transcription polymerase chain reaction and western blot analysis. The EMT‐associated protein expression was determined using the western blot analysis and immunocytochemistry following treatment with various concentrations of DDR1 inhibitor. The activation of DDR1 and also downstream‐signaling molecules Pyk2 and MKK7 were determined using western blot analysis. Cell survival and proliferation after DDR1 inhibition were evaluated using 3‐(4, 5‐dimethylthiazole‐2‐yl)‐2, 5‐diphenyltetrazolium bromide, bromodeoxyuridine, and colony formation assays. Flow cytometry analysis was used to determine the effects of DDR1 inhibition on cell‐cycle arrest and apoptosis using annexin V/propidium iodide‐based flow cytometry. Results showed that the protein expression of N‐cadherin and vimentin were decreased whereas protein expression of E‐cadherin was increased after DDR1 inhibition. Results of our western blot analysis indicated that DDR1 inhibitor effectively downregulated P‐DDR1, P‐Pyk2, and P‐MKK7 levels. This result also showed that DDR1 inhibition decreased cell survival and proliferation, induced G1 cell‐cycle arrest, induced apoptosis by an increase in the Bax/Bcl‐2 ratio and depletion of the mitochondrial membrane potential, and also by reactive oxygen species creation in prostate cancer cells. These data show that DDR1 inhibition can result in the EMT prevention via inhibition of Pyk2 and MKK7 signaling pathway and induces cell‐cycle arrest and apoptosis in prostate cancer cell lines. Thus, this study identifies DDR1 as an important target for modulating EMT and induction of apoptosis in prostate cancer cells. Abstract : We examined the possible effects of DDR1‐IN‐1 as a DDR1 tyrosine kinase inhibitor on epithelial‐mesenchymal transition (EMT), cell‐cycle arrest and apoptosis in prostate cancer cell lines. Our results suggest that inhibition of this receptor may be a potential therapeutic strategy for inhibition of EMT and induction of apoptosis in prostate cancer.