Lens Epithelium-Derived Growth Factor (LEDGF/p75) is a transcriptional co-activator and survival factor in lens epithelium cells (LECs) where it regulates small heat shock proteins (Hsp27 and β-crystalin) and confers resistance to a variety of stress insults including oxidative- and heat stress. We have recently cloned LEDGF/p75 as an Hsp70–2 regulated survival factor in human cancer and shown that it protects epithelial cancer cells from the drug-induced activation of an alternative apoptosis-like cell death pathway that involves destabilization of lysosomes. By using a stable cell line over-expressing LEDGF/p75 we here show that LEDGF/p75 protect cancer cells from cell death induced by a new potential cancer drug named bLAC (bovine α- Lact Albumin Complex) and significantly increases the long-term colony-forming ability of cancer cells after treatment with the lysosome destabilizing drug siramesine. The mechanism by which LEDGF/p75 exerts its survival effect is still unknown but since LEDGF/p75 localize to the nucleus we reasoned that LEDGF/p75 is likely to affect transcription. In a real-time PCR analysis of potential LEDGF/p75 target genes in cancer we failed to see the LEDGF/p75-dependent regulation of small Hsps as evident in LECs. However, ectopic over-expression of LEDGF/p75 promotes a transcriptional up-regulation of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) decoy receptor (DcR2) that is deregulated in several types of cancer and promotes cell survival by neutralizing pro-apoptotic TRAIL-ligand. Importantly and contrary to enforced LEDGF/p75 expression, RNAi-mediated knockdown of LEDGF leads to down-regulation of the DcR2 mRNA suggesting that DcR2 is under direct transcriptional control of LEDGF/p75. Whether DcR2 plays a role in LEDGF/p75-mediated cancer cell survival remains to be elucidated.
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Document Type: Abstract
Apoptoselaboratoriet, Institut for Biologisk Kræftforskning, Kræftens Bekæmpelse, Strandboulevarden 49
NatImmune A/S, Symbion Science Park, Fruebjergvej 3, 2100 København Ø
Publication date: May 1, 2008