Lens epithelium-derived growth factor is an Hsp70-2 regulated guardian of lysosomal stability in human cancer.

Abstract	Heat shock protein 70-2 (Hsp70-2) is a chaperone protein essential for the growth of spermatocytes and cancer cells. Here, we show that Hsp70-2 depletion triggers lysosomal membrane permeabilization and cathepsin-dependent cell death and identify lens epithelium-derived growth factor (LEDGF) as an Hsp70-2-regulated guardian of lysosomal stability in human cancer. Knockdown of LEDGF in cancer cells induces destabilization of lysosomal membranes followed by caspase-independent and Bcl-2-resistant cell death. Accordingly, ectopic LEDGF stabilizes lysosomes and protects cancer cells against cytotoxicity induced by anticancer agents that trigger the lysosomal cell death pathway. Remarkably, ectopic LEDGF also increases the tumorigenic potential of human cancer cells in immunodeficient mice, and LEDGF expression is increased in human breast and bladder carcinomas correlating with that of Hsp70-2 in invasive bladder cancer. Taken together, these data reveal LEDGF as an oncogenic protein that controls a caspase-independent lysosomal cell death pathway.
Authors	Mads Daugaard, Thomas Kirkegaard-Sørensen, Marie Stampe Ostenfeld, Mads Aaboe, Maria Høyer-Hansen, Torben Falck Orntoft, Mikkel Rohde, Marja Jäättelä
Journal	Cancer research (Cancer Res) Vol. 67 Issue 6 Pg. 2559-67 (Mar 15 2007) ISSN: 0008-5472 [Print] United States
PMID	17363574 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Adaptor Proteins, Signal Transducing HSP70 Heat-Shock Proteins HSPA2 protein, human PSIP1 protein, human Transcription Factors
Topics	Adaptor Proteins, Signal Transducing (biosynthesis, deficiency, physiology) Animals Breast Neoplasms (genetics, metabolism, pathology) Cell Death (physiology) Cell Lineage Cell Membrane Permeability Down-Regulation Female HSP70 Heat-Shock Proteins (deficiency, physiology) HeLa Cells Humans Lysosomes (metabolism, pathology) Mice Mice, SCID Transcription Factors (biosynthesis, deficiency, physiology) Transfection Transplantation, Heterologous Urinary Bladder Neoplasms (genetics, metabolism, pathology)

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