Distinct patterns of insulin-like growth factor binding protein (IGFBP)-2 and IGFBP-3 expression in oxidant exposed lung epithelial cells

Abstract

Oxygen (O(2)) species are involved in a large variety of pulmonary diseases. Among the various cell types that compose the lung, the epithelial cells of the alveolar structure appear to be a major target for oxidant injury. Despite their importance in the repair processes, the mechanisms which regulate the replication of the stem cells of the alveolar epithelium, the type 2 cells, remain poorly understood. Based on the results of several studies which have documented the involvement of the insulin-like growth factor (IGF) system in lung epithelial cell replication, and which have also suggested a role for IGF binding proteins (IGFBPs) in the control of cell proliferation, the aim of the present work was to determine whether IGFBPs could be involved in the modulation of growth of human lung epithelial cells exposed to oxidants. Experiments were performed using a human lung adenocarcinoma cell line (A549) which was exposed for various durations to hyperoxia (95% O(2)). We observed a rapid and reversible growth arrest of the cells after only 24 h of O(2) exposure. When oxidant injury was prolonged, growth arrest was followed by induction of apoptosis with activation of the Fas pathway. These effects were associated with an increased expression of IGFBP-2 and IGFBP-3. In addition, study of localization of these proteins revealed distinct patterns of distribution. IGFBP-3 was mainly present in the extracellular compartment. In comparison, the fraction of IGFBP-2 secreted was less abundant whereas the IGFBP-2 fraction in the intracellular compartment appeared stronger. In addition, analysis of the subcellular localization provided data indicating the presence of IGFBP-2 in the nucleus. Taken together these data support a role for IGFBP-2 and IGFBP-3 in the processes of growth arrest and apoptosis in lung epithelial cells upon oxidant exposure. They also suggest that distinct mechanisms may link IGFBP-2 and IGFBP-3 to the key regulators of the cell cycle.

Role of Insulin-Like Growth Factor Binding Protein 2 in Lung Adenocarcinoma

“…Remarkably, IGFBP-2 is predominantly expressed in cytoplasm and nucleus of lung epithelium when exposed to hyperoxia, whereas IGFBP-3 is localized in the extracellular compartment. 60 These findings suggest that IGFBP-2 and -3 may be differentially regulated and also exert a distinct action for cell proliferation and apoptosis in different compartments.…”

Elevated serum levels of IGF-binding protein 2 in patients with non-seminomatous germ cell cancer: correlation with tumor markers α-fetoprotein and human chorionic gonadotropin

“…However, IGFBP-2 overexpression is not a phenomenon confined to testicular cancer and increased IGFBP-2 levels are not specific for indicating tumor disease, since an elevation of IGFBP-2 can be found in various different other conditions, usually associated with oxidative stress (33)(34)(35), where increased IGFBP-2 expression was used to activate defense mechanisms. These observations led to the question of whether the frequently observed overexpression of IGFBP-2 in malignant tumors is the cause of tumor formation or rather the consequence.…”

Insulin-like growth factor binding protein-2 is a novel mediator of p53 inhibition of insulin-like growth factor signaling

“…IGF-independent activities of IGFBP-2 have been suggested by its interactions with α5β1-integrin, 40 its cytosolic uptake, 41 and its nuclear translocation. 42,43 Although IGFBP-2 has been shown to inhibit proliferation in multiple cell lines in IGF-dependent cell culture systems, 41 experimentally created IGFBP-2 overexpression in vitro increased invasiveness of ovarian 44 and bladder 45 cancer cell lines, and increased proliferation of Y-1 murine adrenocortical tumor cells 46 and DU145 prostate cancer cells. 47 IGFBP-2 expression has been shown to be elevated in multiple tumors (including prostate, colon, adrenocortical, mammary, ovarian, brain, thyroid, and hepatic cancers), to often correlate positively with tumor grade and/or stage and to be increased in the serum of these patients.…”