MARCKS cooperates with NKAP to activate NF-kB signaling in smoke-related lung cancer.

Cigarette smoking is a major risk factor for lung cancer development and progression; however, the mechanism of how cigarette smoke activates signaling pathways in promoting cancer malignancy remains to be established. Herein, we aimed to determine the contribution of a signaling protein, myristoylated alanine-rich C kinase substrate (MARCKS), in smoke-mediated lung cancer. We firstly examined the levels of phosphorylated MARCKS (phospho-MARCKS) in smoke-exposed human lung cancer cells and specimens as well as non-human primate airway epithelium.

Targeting the AXL Receptor in Combating Smoking-related Pulmonary Fibrosis.

Tobacco smoking is a well-known risk factor for both fibrogenesis and fibrotic progression; however, the mechanisms behind these processes remain enigmatic. RTKs (receptor tyrosine kinases) have recently been reported to drive profibrotic phenotypes in fibroblasts during pulmonary fibrosis (PF). Using a phospho-RTK array screen, we identified the RTK AXL as a top upregulated RTK in response to smoke.

Metabolic reprogramming: A driver of cigarette smoke-induced inflammatory lung diseases.

Cigarette smoking is a well-known risk factor for pulmonary diseases, including chronic obstructive pulmonary disease (COPD), asthma and pulmonary fibrosis. Despite major progress in dissecting the mechanisms associated with disease development and progression, findings only represent one aspect of multifaceted disease. A crucial consequence of this approach is that many therapeutic treatments often fail to improve or reverse the disease state as other conditions and variables are insufficiently considered.

Cigarette Smoking-Mediated Macrophage Reprogramming: Mechanistic Insights and Therapeutic Implications.

Macrophages, the mature form of the monocytes, play a significant role in tissue homeostasis and immunity. In response to environmental cues, they can undergo classical or alternative activation, polarizing into specialized functional subsets. A common hallmark of the pathologic environment is represented by cigarette smoking.

Cigarette Smoke Regulates the Competitive Interactions between NRF2 and BACH1 for Heme Oxygenase-1 Induction.

Cigarette smoke has been shown to trigger aberrant signaling pathways and pathophysiological processes; however, the regulatory mechanisms underlying smoke-induced gene expression remain to be established. Herein, we observed that two smoke-responsive genes, and , are robustly induced upon smoke by different mechanisms in human bronchial epithelia. is mediated by aryl hydrocarbon receptor signaling, while induction of is regulated by oxidative stress, and suppressed by -acetylcysteine treatment.

Myristoylated alanine-rich C kinase substrate (MARCKS): a multirole signaling protein in cancers.

Emerging evidence implicates myristoylated alanine-rich C-kinase substrate (MARCKS), a major substrate of protein kinase C (PKC), in a critical role for cancer development and progression. MARCKS is tethered to the plasma membrane but can shuttle between the cytosol and plasma membrane via the myristoyl-electrostatic switch. Phosphorylation of MARCKS by PKC leads to its translocation from the plasma membrane to the cytosol where it functions in actin cytoskeletal remodeling, Ca signaling through binding to calmodulin, and regulation of exocytic vesicle release in secretory cells such as neurons and airway goblet cells.

Upregulation of MARCKS in kidney cancer and its potential as a therapeutic target.

Targeted therapeutics, such as those abrogating hypoxia inducible factor (HIF)/vascular endothelial growth factor signaling, are initially effective against kidney cancer (or renal cell carcinoma, RCC); however, drug resistance frequently occurs via subsequent activation of alternative pathways. Through genome-scale integrated analysis of the HIF-α network, we identified the major protein kinase C substrate MARCKS (myristoylated alanine-rich C kinase substrate) as a potential target molecule for kidney cancer. In a screen of nephrectomy samples from 56 patients with RCC, we found that MARCKS expression and its phosphorylation are increased and positively correlate with tumor grade.

HLJ1 is an endogenous Src inhibitor suppressing cancer progression through dual mechanisms.

HLJ1 (DNAJB4), a DNAJ/Hsp40 chaperone, has emerged as a novel prognostic marker in lung cancers; however, the molecular contribution and functionality in neoplastic diseases remain to be established. This study demonstrated that HLJ1 inhibits epithelial-mesenchymal transition in vitro and reduces lung cancer metastasis in vivo. Using shRNA silencing and ectopic expression of HLJ1, we found that HLJ1 not only suppresses catalytic activity of Src but also downregulates the formation of oncogenic complexes associated with the EGFR, FAK and STAT3 signaling pathways.

Elevated MARCKS phosphorylation contributes to unresponsiveness of breast cancer to paclitaxel treatment.

Accumulating evidence has suggested that myristoylated alanine-rich C-kinase substrate (MARCKS) is critical for regulating multiple pathophysiological processes. However, the molecular mechanism underlying increased phosphorylation of MARCKS at Ser159/163 (phospho-MARCKS) and its functional consequence in neoplastic disease remain to be established. Herein, we investigated how phospho-MARCKS is regulated in breast carcinoma, and its role in the context of chemotherapy.

Erlotinib-cisplatin combination inhibits growth and angiogenesis through c-MYC and HIF-1α in EGFR-mutated lung cancer in vitro and in vivo.

Combination treatment for non-small cell lung cancer (NSCLC) is becoming more popular due to the anticipation that it may be more effective than single drug treatment. In addition, there are efforts to genetically screen patients for specific mutations in light of attempting to administer specific anticancer agents that are most effective. In this study, we evaluate the anticancer and anti-angiogenic effects of low dose erlotinib-cisplatin combination in NSCLC in vitro and in vivo.

Targeting myristoylated alanine-rich C kinase substrate phosphorylation site domain in lung cancer. Mechanisms and therapeutic implications.

Rationale: Phosphorylation of myristoylated alanine-rich C kinase substrate (phospho-MARCKS) at the phosphorylation site domain (PSD) is crucial for mucus granule secretion and cell motility, but little is known concerning its function in lung cancer.

Objectives: We aimed to determine if MARCKS PSD activity can serve as a therapeutic target and to elucidate the molecular basis of this potential.

Methods: The clinical relevance of phospho-MARCKS was first confirmed.

A peptide that inhibits function of Myristoylated Alanine-Rich C Kinase Substrate (MARCKS) reduces lung cancer metastasis.

Myristoylated Alanine-Rich C Kinase Substrate (MARCKS), a substrate of protein kinase C, is a key regulatory molecule controlling mucus granule secretion by airway epithelial cells as well as directed migration of leukocytes, stem cells and fibroblasts. Phosphorylation of MARKCS may be involved in these responses. However, the functionality of MARCKS and its related phosphorylation in lung cancer malignancy have not been characterized.

The Basement Membrane Zone in Asthma: The Supracellular Anchoring Network.

Thickening of the basement membrane zone (BMZ) is a characteristic feature of airway remodeling in the lungs of asthmatics. However the significance of a thickened BMZ in the pathology of the asthmatic airway is not known. In this review we show that the columnar epithelium is linked to the reticular BMZ through the supracellular anchoring network.

Innate immune response to LPS in airway epithelium is dependent on chronological age and antecedent exposures.

The immune mechanisms for neonatal susceptibility to respiratory pathogens are poorly understood. Given that mucosal surfaces serve as a first line of host defense, we hypothesized that the innate immune response to infectious agents may be developmentally regulated in airway epithelium. To test this hypothesis, we determined whether the expression of IL-8 and IL-6 in airway epithelium after LPS exposure is dependent on chronological age.

Evaluation of MUC5AC expression and upregulation in airway epithelial cells of horses.

Objective: To isolate and culture primary equine airway epithelial cells in vitro and elucidate the major cytokines involved in expression of the gel-forming mucin gene MUC5AC in horses.

Sample Population: 12 tracheas obtained within 5 hours after euthanasia from horses free from respiratory tract disease.

Procedures: Tracheal rings were digested overnight in 0.

Reduction of collagen VII anchoring fibrils in the airway basement membrane zone of infant rhesus monkeys exposed to house dust mite.

Collagen VII anchoring fibrils in the basement membrane zone (BMZ) are part of a supracellular anchoring network that attaches the epithelium to the BMZ. Sloughing of airway epithelium in asthmatics (creola bodies) is a pathology associated with the supracellular anchoring network. In a rhesus monkey model of house dust mite (HDM)-induced allergic asthma, we found increased deposition of collagen I in the BMZ.

Enhanced inflammatory responses in alpha-tocopherol transfer protein null mice.

The liver preferentially secretes alpha-tocopherol into plasma under the control of the hepatic alpha-tocopherol transfer protein (alpha-TTP). alpha-TTP-null mice (Ttpa(-/-) mice) are vitamin E deficient, therefore were used for investigations of in vivo responses to sub-normal tissue alpha-tocopherol concentrations during inflammation. Increased basal oxidative stress in Ttpa(-/-) mice was documented by increased plasma lipid peroxidation, and superoxide production by bone marrow-derived neutrophils stimulated in vitro with phorbol 12-myristate 13-acetate.

Expression of the beta6 integrin subunit is associated with sites of neutrophil influx in lung epithelium.

Inhalation of ozone by Rhesus monkeys results in epithelial injury and granulocyte influx in both conducting airways and respiratory bronchioles. We have reported that ozone-induced neutrophil recruitment and subsequent epithelial repair can be inhibited in vivo with a CD18 antibody. The antibody-mediated effect is abrogated by local instillation of C5a (a CD18-independent neutrophil chemoattractant), thereby demonstrating a role for neutrophils in lung epithelial repair processes.

Three-dimensional organization of the lamina reticularis in the rat tracheal basement membrane zone.

The airway basement membrane zone is a region specialized for the attachment of the epithelium with the matrix. The epithelium is attached to the lamina densa, which, in turn, is connected to types I and III collagen of the lamina reticularis with anchoring fibrils. The purpose of this study was to define the three-dimensional organization of the structural proteins of the lamina reticularis in the rat trachea.

Neutrophils enhance clearance of necrotic epithelial cells in ozone-induced lung injury in rhesus monkeys.

To test the hypothesis that neutrophil influx is important for the removal of necrotic airway epithelial cells, rhesus monkeys were treated with a function-blocking monoclonal antibody (MAb) against CD18 followed by exposure to ozone or filtered air. CD18 MAb-treated, ozone-exposed monkeys showed a significant inhibition of neutrophil emigration and an accumulation of necrotic airway epithelial cells. In a subsequent experiment, monkeys were given CD18 MAb or an isotype control immunoglobulin before ozone or filtered-air exposure.