Lens epithelium-derived growth factor is an Hsp70-2 regulated guardian of lysosomal stability in human cancer.
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.
Daugaard
Mads
M
Apoptosis Department, Danish Centre for Translational Breast Cancer Research, Institute of Cancer Biology, Danish Cancer Society, Copenhagen, Denmark.
Kirkegaard-Sørensen
Thomas
T
Ostenfeld
Marie Stampe
MS
Aaboe
Mads
M
Høyer-Hansen
Maria
M
Orntoft
Torben Falck
TF
Rohde
Mikkel
M
Jäättelä
Marja
M
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death / Q000502:physiology; D019070:Cell Lineage; D002463:Cell Membrane Permeability; D015536:Down-Regulation; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000172:deficiency / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D014157:Transcription Factors / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D014162:Transfection; D014183:Transplantation, Heterologous; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
D048868:Adaptor Proteins, Signal Transducing; D018840:HSP70 Heat-Shock Proteins; C091879:HSPA2 protein, human; C504649:PSIP1 protein, human; D014157:Transcription Factors