Neutrophil gelatinase-associated lipocalin as a survival factor

Biochem J. 2005 Oct 15;391(Pt 2):441-8. doi: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3-Phosphoinositide-Dependent Protein Kinases
  • Acute-Phase Proteins / genetics
  • Acute-Phase Proteins / metabolism*
  • Apoptosis*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Down-Regulation / drug effects
  • Gene Expression Regulation / drug effects
  • Humans
  • Indoles / pharmacology
  • Lipocalin-2
  • Lipocalins
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Pyrazoles / pharmacology
  • Pyrazoles / toxicity
  • RNA, Messenger / metabolism
  • Sulfonamides / pharmacology
  • Sulfonamides / toxicity
  • Up-Regulation / drug effects

Substances

  • Acute-Phase Proteins
  • Indoles
  • LCN2 protein, human
  • Lipocalin-2
  • Lipocalins
  • OSU 03012
  • Proto-Oncogene Proteins
  • Pyrazoles
  • RNA, Messenger
  • Sulfonamides
  • MK-886
  • 3-Phosphoinositide-Dependent Protein Kinases
  • PDPK1 protein, human
  • Pdpk1 protein, mouse
  • Protein-Serine-Threonine Kinases