PKR-Mediated Phosphorylation of eIF2a and CHK1 Is Associated with Doxorubicin-Mediated Apoptosis in HCC1143 Triple-Negative Breast Cancer Cells

Abstract

Triple-negative breast cancer is more aggressive than other types of breast cancer. Protein kinase R (PKR), which is activated by dsRNA, is known to play a role in doxorubicin-mediated apoptosis; however, its role in DNA damage-mediated apoptosis is not well understood. In this study, we investigated the roles of PKR and its downstream players in doxorubicin-treated HCC1143 triple-negative breast cancer cells. Doxorubicin treatment induces DNA damage and apoptosis. Interestingly, doxorubicin treatment induced the phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α) via PKR, whereas the inhibition of PKR with inhibitor C16 reduced eIF2α phosphorylation. Under these conditions, doxorubicin-mediated DNA fragmentation, cell death, and poly(ADP ribose) polymerase and caspase 7 levels were recovered. In addition, phosphorylation of checkpoint kinase 1 (CHK1), which is known to be involved in doxorubicin-mediated DNA damage, was increased by doxorubicin treatment, but blocked by PKR inhibition. Protein translation was downregulated by doxorubicin treatment and upregulated by blocking PKR phosphorylation. These results suggest that PKR activation induces apoptosis by increasing the phosphorylation of eIF2α and CHK1 and decreasing the global protein translation in doxorubicin-treated HCC1143 triple-negative breast cancer cells.

Smooth Muscle Cell Phenotypic Switch Induced by Traditional Cigarette Smoke Condensate: A Holistic Overview

“…PKR is implied in a plethora of cellular functions spanning from signal transduction and apoptosis, to cell proliferation and differentiation, by modulating p53/TP53, PPP2R5A, ILF3, and IRS1 activities [ 25 , 26 , 27 , 28 ], and by regulating various signaling pathways, such as p38 mitogen-activated protein kinase (p38 MAPK), NF-kB, and insulin signaling pathways, as well as of transcription factors, e.g., JUK, STAT1, STAT3, IRF1, and ATF3, involved in gene expression of pro-inflammatory cytokines and IFNs [ 29 , 30 ]. Although studies on PKR in SMCs have only recently intensified [ 31 ], several of PKR’s known activities underline a close and multilevel correlation between the increase in its expression and the biochemical and phenotypic changes we described in HSMC after CSC treatment.…”