Increased expression of the lipocalin 24p3 as an apoptotic mechanism for MK886

Abstract

MK886, a strong proapoptotic agent, is an inhibitor of 5-lipoxygenase (LOX) through binding to the 5-LOX-activating protein (FLAP). Although MK886-induced apoptosis is through a FLAP-independent pathway, the precise mechanisms are not understood. In the present study, a possible role of 24p3, a lipocalin, in MK886-induced apoptosis was investigated. Exposure of murine prolymphoid progenitor cells (FL5.12) to 20 microM MK886 for 16 h dramatically increased 24p3 mRNA and protein expression. Induction could also be achieved with another FLAP inhibitor, MK591. The induction of 24p3 by MK886 was dose- and time-dependent. The up-regulated 24p3 mRNA expression by MK886 was enhanced a further 3.1-fold by WY14643, an activator of peroxisome-proliferator-activated receptor alpha, whereas ciglitazone, an activator of peroxisome-proliferator-activated receptor gamma attenuated the MK886-induced 24p3 expression by more than 50%. Neither WY14643 nor ciglitazone alone had any effect on the expression of 24p3. The induction of 24p3 by MK886 was dependent on the synthesis of new protein(s), since cycloheximide, an inhibitor of protein synthesis, prevented this effect. In all cases, including the inhibition of MK886-induced 24p3 protein expression by stable transfection with antisense cDNA of 24p3, the extent of apoptosis closely paralleled 24p3 levels. Apoptosis induced by MK886, or enhanced by WY14643, was accompanied by the cleavage and activation of caspase-3. The overexpression of bcl-2 or bcl-x(L) in FL5.12 cells inhibited apoptosis induced by MK886 as well as the enhancement of apoptosis by WY14643. Thus 24p3 is an MK886-inducible gene and may play an important role in MK886-induced apoptosis.

A Dual Role of Lipocalin 2 in the Apoptosis and Deramification of Activated Microglia

“…6C). Bcl-2 family proteins have been previously implicated in the effects of lcn2 on the cell death and survival (28,29,31). In particular, up-regulation of proapoptotic Bim expression was essential for the apoptosis-inducing effects of lcn2 (29).…”

Lipocalin-2 Is an Autocrine Mediator of Reactive Astrocytosis

“…These results indicate that the cell death-sensitizing activity of lcn2 in astrocytes is related to the iron transport and metabolism: apo-lcn2 may promote cell death by depleting intracellular iron, whereas holo-lcn2 containing the siderophore-iron complex may not. Bcl-2 family proteins have been previously implicated in the effects of lcn2 on cell death and survival (Yousefi and Simon, 2002;Tong et al, 2003;Devireddy et al, 2005). In particular, the upregulation of proapoptotic Bim expression was essential for the apoptosisinducing effects of lcn2 (Devireddy et al, 2005).…”

“…lcn2 is also known as 24p3 and neutrophil gelatinase-associated lipocalin (NGAL) (Borregaard and Cowland, 2006). In vitro studies have shown that lcn2 is important for both cellular apoptosis and survival (Devireddy et al, 2001(Devireddy et al, , 2005Yousefi and Simon, 2002;Tong et al, 2003Tong et al, , 2005Nelson et al, 2008). It also plays an important role in the induction of cellular differentiation in kidney during embryogenesis (Yang et al, 2002) and protects the kidney from ischemic injury (Mishra et al, 2004;Mori et al, 2005).…”

Lipocalin-2 Regulates the Inflammatory Response During Ischemia and Reperfusion of the Transplanted Heart

“…Lipocalins are part of a large family of proteins involved in the regulation of diverse cellular processes, partially with diverse outcomes (12). Lcn-2 is highly expressed during acute microbial infection as well as tissue involution, and has been shown recently to induce apoptosis of hematopoietic cells (13)(14)(15)(16)(17). However, work on Lcn-2 also suggested a role as mediator of cell growth and viability (18).…”

“…The expression of Lcn-2 in nonheart tissues was described by several authors with emphasis on epithelial and hematopoietic cell lines (human lung adenocarcinoma A549 cells, human breast cancer MCF7 cells (13), hematopoietic FL5.12 (14) and 32D (33) cells, etc. ), murine and human tissues (epithelium of lung (34), bowel (35), uterus (28), mammary epithelial cells (36), tubular epithelium of the kidney (37), adenocarcinoma of the breast, ovary and pancreas (38), leukocytes (39), etc.)…”