This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Daugaard, M. Articles by Jäättelä, M. Search for Related Content PubMed PubMed Citation Articles by Daugaard, M. Articles by Jäättelä, M.

Lens Epithelium-Derived Growth Factor Is an Hsp70-2 Regulated Guardian of Lysosomal Stability in Human Cancer

¹ Apoptosis Department, Danish Centre for Translational Breast Cancer Research and Centre for Genotoxic Stress Research, Institute of Cancer Biology, Danish Cancer Society, Copenhagen, Denmark and ² Department of Clinical Biochemistry, Aarhus University Hospital, Skejby, Aarhus, Denmark

Requests for reprints: Marja Jäättelä, Apoptosis Department, Institute for Cancer Biology, Danish Cancer Society, Strandboulevarden 49, DK-2100 Copenhagen, Denmark. Phone: 45-35257318; Fax: 45-35257721; E-mail: mj{at}cancer.dk.

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. [Cancer Res 2007;67(6):2559–67]

This article has been cited by other articles:

				K. Bartholomeeusen, F. Christ, J. Hendrix, J.-C. Rain, S. Emiliani, R. Benarous, Z. Debyser, R. Gijsbers, and J. De Rijck Lens Epithelium-derived Growth Factor/p75 Interacts with the Transposase-derived DDE Domain of PogZ J. Biol. Chem., April 24, 2009; 284(17): 11467 - 11477. [Abstract] [Full Text] [PDF]

				V. L. Gabai, J. A. Yaglom, T. Waldman, and M. Y. Sherman Heat Shock Protein Hsp72 Controls Oncogene-Induced Senescence Pathways in Cancer Cells Mol. Cell. Biol., January 15, 2009; 29(2): 559 - 569. [Abstract] [Full Text] [PDF]

				A. A. Karaczyn, R. Y. S. Cheng, G. S. Buzard, J. Hartley, D. Esposito, and K. S. Kasprzak Truncation of Histone H2A's C-terminal Tail, as Is Typical for Ni(II)-Assisted Specific Peptide Bond Hydrolysis, Has Gene Expression Altering Effects Ann. Clin. Lab. Sci., January 1, 2009; 39(3): 251 - 262. [Abstract] [Full Text] [PDF]

				T. Sasaki, E. Marcon, T. McQuire, Y. Arai, P. B. Moens, and H. Okada Bat3 deficiency accelerates the degradation of Hsp70-2/HspA2 during spermatogenesis J. Cell Biol., August 11, 2008; 182(3): 449 - 458. [Abstract] [Full Text] [PDF]

				T. A. Brown-Bryan, L. S. Leoh, V. Ganapathy, F. J. Pacheco, M. Mediavilla-Varela, M. Filippova, T. A. Linkhart, R. Gijsbers, Z. Debyser, and C. A. Casiano Alternative Splicing and Caspase-Mediated Cleavage Generate Antagonistic Variants of the Stress Oncoprotein LEDGF/p75 Mol. Cancer Res., August 1, 2008; 6(8): 1293 - 1307. [Abstract] [Full Text] [PDF]