Neutrophil gelatinase-associated lipocalin as a survival factor
- 10 October 2005
- journal article
- Published by Portland Press Ltd. in Biochemical Journal
- Vol. 391 (2), 441-448
- https://doi.org/10.1042/bj20051020
Abstract
NGAL (human neutrophil gelatinase-associated lipocalin) and its mouse analogue 24p3 are members of the lipocalin family of small secreted proteins. These proteins are up-regulated in a number of pathological conditions, including cancers, and may function as transporters of essential factors. Although previous publications have suggested that 24p3 has pro-apoptotic functions, other data are more suggestive of a survival function. The current study was designed to determine whether NGAL is pro- or anti-apoptotic. Apoptosis induced in human adenocarcinoma A549 cells by the 5-lipoxygenase-activating-protein inhibitor MK886, or several celecoxib-derived PDK1 (phosphoinositide-dependent kinase 1) inhibitors that are devoid of cyclo-oxygenase-2 inhibitory activity, was accompanied by a dose- and time-dependent increase of NGAL mRNA levels, as was reported previously with 24p3. A similar induction of NGAL mRNA was observed in human breast cancer MCF7 cells treated with MK886, indicating this was not a cell-specific effect. Treatment of A549 cells with up to 150 mug/10(6) cells of purified recombinant NGAL protein had no effect on viability, whereas antisera against the full-length NGAL protein induced apoptosis in these cells. The stable overexpression of NGAL in A549 cells had no effect on proliferation or viability. However, the cell death induced by a PDK1 inhibitor was reduced by 50% in NGAL-overexpressing cells. Decreasing NGAL mRNA and protein expression with siRNA (small interfering RNA) in A549 cells increased the toxicity of a PDK1 inhibitor by approx. 45%. These data indicate that, although the induction of NGAL correlates with apoptosis, this induction represents a survival response. Because NGAL is a secreted protein, it may play an extracellular role in cell defence against toxicants and/or facilitate the survival of the remaining cells.This publication has 41 references indexed in Scilit:
- Amelioration of Ischemic Acute Renal Injury by Neutrophil Gelatinase-Associated LipocalinJournal of the American Society of Nephrology, 2004
- Epidermal Growth Factor Receptor-dependent, NF-κB-independent Activation of the Phosphatidylinositol 3-Kinase/Akt Pathway Inhibits Ultraviolet Irradiation-induced Caspases-3, -8, and -9 in Human KeratinocytesOnline Journal of Public Health Informatics, 2003
- Hypoxia induces an autocrine‐paracrine survival pathway via platelet‐derived growth factor (PDGF)‐B/PDGF‐β receptor/phosphatidylinositol 3‐kinase/Akt signaling in RN46A neuronal cellsThe FASEB Journal, 2003
- Inhibition of cell proliferation and induction of apoptosis byExFABP gene targetingJournal of Cellular Physiology, 2003
- Induction of Apoptosis by a Secreted Lipocalin That is Transcriptionally Regulated by IL-3 DeprivationScience, 2001
- Human tear lipocalin acts as an oxidative-stress-induced scavenger of potentially harmful lipid peroxidation products in a cell culture systemBiochemical Journal, 2001
- Lipocalins and cancerBiochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology, 2000
- The Effect of Celecoxib, a Cyclooxygenase-2 Inhibitor, in Familial Adenomatous PolyposisThe New England Journal of Medicine, 2000
- An Adaptationist View of ApoptosisThe Quarterly Review of Biology, 1997
- Cloning and expression of human neutrophil lipocalin cDNA derived from bone marrow and ovarian cancer cellsFEBS Letters, 1995