title: Double-stranded RNA-dependent protein kinase regulates the motility of breast cancer cells.
abstract: Double-stranded RNA (dsRNA)-dependent protein kinase (PKR) is an interferon-induced protein kinase that plays a central role in the anti-viral process. Due to its pro-apoptotic and anti-proliferative action, there is an increased interest in PKR modulation as an anti-tumor strategy. PKR is overexpressed in breast cancer cells; however, the role of PKR in breast cancer cells is unclear. The expression/activity of PKR appears inversely related to the aggressiveness of breast cancer cells. The current study investigated the role of PKR in the motility/migration of breast cancer cells. The activation of PKR by a synthesized dsRNA (PIC) significantly decreased the motility of several breast cancer cell lines (BT474, MDA-MB231 and SKBR3). PIC inhibited cell migration and blocked cell membrane ruffling without affecting cell viability. PIC also induced the reorganization of the actin cytoskeleton and impaired the formation of lamellipodia. These effects of PIC were reversed by the pretreatment of a selective PKR inhibitor. PIC also activated p38 mitogen-activated protein kinase (MAPK) and its downstream MAPK-activated protein kinase 2 (MK2). PIC-induced activation of p38 MAPK and MK2 was attenuated by the PKR inhibitor and the PKR siRNA, but a selective p38 MAPK inhibitor (SB203580) or other MAPK inhibitors did not affect PKR activity, indicating that PKR is upstream of p38 MAPK/MK2. Cofilin is an actin severing protein and regulates membrane ruffling, lamellipodia formation and cell migration. PIC inhibited cofilin activity by enhancing its phosphorylation at Ser3. PIC activated LIM kinase 1 (LIMK1), an upstream kinase of cofilin in a p38 MAPK-dependent manner. We concluded that the activation of PKR suppressed cell motility by regulating the p38 MAPK/MK2/LIMK/cofilin pathway.
authors.affiliation: Department of Internal Medicine, University of Kentucky College of Medicine, Lexington, Kentucky, United States of America.
authors.forename: Mei
authors.initials: M
authors.lastname: Xu
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Siying
authors.initials: S
authors.lastname: Wang
authors.forename: Mingjun
authors.initials: M
authors.lastname: Liao
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Frank
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Bower
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Zhang
authors.forename: Xianglin
authors.initials: X
authors.lastname: Shi
authors.forename: Jia
authors.initials: J
authors.lastname: Luo
mesh_terms: D051339:Actin Depolymerizing Factors / Q000378:metabolism; D001940:Breast / Q000166:cytology / Q000201:enzymology / Q000473:pathology; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000201:enzymology / Q000473:pathology; D002465:Cell Movement; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D054461:Lim Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D019892:eIF-2 Kinase / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D051339:Actin Depolymerizing Factors; D047908:Intracellular Signaling Peptides and Proteins; D054461:Lim Kinases; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C515892:LIMK1 protein, human