Role of protein kinase C-η in cigarette smoke extract-induced apoptosis in MRC-5-cells

Abstract

<jats:p> Cigarette smoke (CS) is a major risk factor for emphysema, which causes cell death in structural cells of the lung by mechanisms that are still not completely understood. We demonstrated previously that CS extract (CSE) induces caspase activation in MRC-5 human lung fibroblasts, activated protein kinase C-η (PKC-η), and translocated PKC-η from the cytosol to the membrane. The objective of this study was to investigate the involvement of PKC-η activation in a CSE-induced extrinsic apoptotic pathway. We determined that CSE increases expression of caspase 3 and 8 cleavage in MRC-5 cells and overexpression of PKC-η significantly increased expression of caspase 3 and 8 cleavage compared with control LacZ-infected cells. In contrast, dominant negative (dn) PKC-η inhibited apoptosis in MRC-5 cells exposed to CSE and decreased expression of caspase 3 and 8 compared with control cells. Exposure to 10% CSE for &gt;8 h significantly increased lactate dehydrogenase release in PKC-η-infected cells compared with LacZ-infected cells. Additionally, PKC-η-infected cells had an increased number of Hoechst 33342 stained nuclei compared with LacZ-infected cells, while dn PKC-η-infected cells exhibited fewer morphological changes than LacZ-infected cells under phase-contrast microscopy. In conclusion, PKC-η activation plays a pro-apoptotic role in CSE-induced extrinsic apoptotic pathway in MRC-5 cells. These results suggest that modulation of PKC-η may be a useful tool for regulating the extrinsic apoptosis of MRC-5 cells by CSE and may have therapeutic potential in the treatment of CS-induced lung injury. </jats:p>

Carbonyl Compounds in the Gas Phase of Cigarette Mainstream Smoke and Their Pharmacological Properties

“…22) Activation and translocation of PKCη to the plasma membrane are essential for CSE-induced apoptosis via upregulation of caspase 3 and 8 in human lung fibroblasts (MRC-5 cells). 23) In addition, CSE-induced apoptosis of MRC-5 cells is inhibited by PKCα but promoted by PKCζ. 24) PKCε activation in response to coexposure to cigarette smoke and alcohol decreases airway epithelial cell cilia beating.…”

Lung Fibroblasts from Chronic Obstructive Pulmonary Disease Subjects Have a Deficient Gene Expression Response to Cigarette Smoke Extract Compared to Healthy

“…Other research has shown that exposure to CSE increases inflammation, 5 and inhibits the proliferation and migration in healthy lung fibroblasts 8 CSE has also been shown to induce senescence, increase collagen production, and increase apoptosis and necrosis (at CSE concentrations above 40%) in healthy lung fibroblasts. [9][10][11][12] Although these studies only investigated a narrow range of variables, CSE clearly affects healthy (or cell line) lung fibroblast cells; however, the effects of CSE on lung fibroblasts from COPD subjects are still poorly understood. A concerning note is that many studies assume that healthy lung fibroblasts will respond to CSE the same way as COPD lung fibroblasts that may present false-positive biomarkers of interest for COPD.…”

Identification of Phytoconstituents as Potent Inhibitors of Casein Kinase-1 Alpha Using Virtual Screening and Molecular Dynamics Simulations

“…Like other kinases, CK1α performs multiple biological processes such as cell division, cell cycle, beta-catenin destruction and cell morphogenesis, signal transduction, WNT signaling pathway, etc. [8][9][10][11][12][13][14]. Pharmacological inhibition of CK1α has been investigated as a potential therapy in various diseases, including cancers [15].…”