Signalling via integrins: implications for cell survival and anticancer strategies.
ABSTRACT Integrin-associated signalling renders cells more resistant to genotoxic anti-cancer agents like ionizing radiation and chemotherapeutic substances, a phenomenon termed cell adhesion-mediated radioresistance/drug resistance (CAM-RR, CAM-DR). Integrins are heterodimeric cell-surface molecules that on one side link the actin cytoskeleton to the cell membrane and on the other side mediate cell-matrix interactions. In addition to their structural functions, integrins mediate signalling from the extracellular space into the cell through integrin-associated signalling and adaptor molecules such as FAK (focal adhesion kinase), ILK (integrin-linked kinase), PINCH (particularly interesting new cysteine-histidine rich protein) and Nck2 (non-catalytic (region of) tyrosine kinase adaptor protein 2). Via these molecules, integrin signalling tightly and cooperatively interacts with receptor tyrosine kinase signalling to regulate survival, proliferation and cell shape as well as polarity, adhesion, migration and differentiation. In tumour cells of diverse origin like breast, colon or skin, the function and regulation of these molecules is partly disturbed and thus might contribute to the malignant phenotype and pre-existent and acquired multidrug resistance. These issues as well as a variety of therapeutic options envisioned to influence tumour cell growth, metastasis and resistance, including kinase inhibitors, anti-integrin antibodies or RNA interference, will be summarized and discussed in this review.
- [Show abstract] [Hide abstract]
ABSTRACT: It is well known that tumor microenvironment play a vital role in drug resistance and cell adhesion-mediated drug-resistance (CAM-DR),which is a form of de novo drug resistance. In previous study, we reported that MGr1-Ag/37LRP ligation-induced adhesion and participated in protecting gastric cancer cells from a number of apoptotic stimuli caused by chemotherapeutic drugs. Further study suggested that MGr1-Ag could prompt CAM-DR via interaction with laminin(LN). However, the MGr1-Ag-initiated intracellular signal transduction pathway is still unknown. In this study, our experimental results showed that gastric cancer multidrug resistance (MDR) cell lines mediated CAM-DR via up-regulation of Bcl-2 by MGr1-Ag interaction with LN. Further study found that, as a receptor of ECM components, MGr1-Ag/37LRP may activate the downstream signal pathway PI3K/AKT and MAPK/ERK via the interaction with pFAK. Moreover, the sensitivity to chemotherapeutic drug could be significantly enhanced by inhibiting MGr1-Ag/37LRP expression via mcAb, siRNA and ASO. According to above results, we concluded that FAK/PI3K and MAPK signal pathway play an important role in MGr1-Ag mediated CAM-DR in gastric cancer. MGr1-Ag/37LRP might be a potential effective reversal target to MDR of gastric cancer.This article is protected by copyright. All rights reserved.Cancer Science 04/2014; · 3.48 Impact Factor
Article: Pathogenesis of liver fibrosis.[Show abstract] [Hide abstract]
ABSTRACT: Liver fibrosis is a major cause of morbidity and mortality worldwide due to chronic viral hepatitis and, more recently, from fatty liver disease associated with obesity. Hepatic stellate cell activation represents a critical event in fibrosis because these cells become the primary source of extracellular matrix in liver upon injury. Use of cell-culture and animal models has expanded our understanding of the mechanisms underlying stellate cell activation and has shed new light on genetic regulation, the contribution of immune signaling, and the potential reversibility of the disease. As pathways of fibrogenesis are increasingly clarified, the key challenge will be translating new advances into the development of antifibrotic therapies for patients with chronic liver disease.Annual Review of Pathology Mechanisms of Disease 01/2010; 6:425-56. · 25.79 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Studies have demonstrated that reactive oxygen species (ROS) generated by NADPH oxidase are essential for melanoma proliferation and survival. However, the mechanisms by which NADPH oxidase regulates these effects are still unclear. In this work, we investigate the role of NADPH oxidase-derived ROS in the signaling events that coordinate melanoma cell survival. Using the highly metastatic human melanoma cell line MV3, we observed that pharmacological NADPH oxidase inhibition reduced melanoma viability and induced dramatic cellular shape changes. These effects were accompanied by actin cytoskeleton rearrangement, diminished FAKY397 phosphorylation, and decrease of FAK-actin and FAK-cSrc association, indicating disassembly of focal adhesion processes, a phenomenon that often results in anoikis. Accordingly, NADPH oxidase inhibition also enhanced hypodiploid DNA content, and caspase-3 activation, suggesting activation of the apoptotic machinery. NOX4 is likely to be involved in these effects, since silencing of NOX4 significantly inhibited basal ROS production, reduced FAKY397 phosphorylation and decreased tumor cell viability. Altogether, the results suggest that intracellular ROS generated by the NADPH oxidase, most likely NOX4, transmits cell survival signals on melanoma cells through the FAK pathway, maintaining adhesion contacts and cell viability.PLoS ONE 01/2014; 9(6):e99481. · 3.53 Impact Factor