title: Inhibiting the HSP90 chaperone destabilizes macrophage migration inhibitory factor and thereby inhibits breast tumor progression.
abstract: Intracellular macrophage migration inhibitory factor (MIF) often becomes stabilized in human cancer cells. MIF can promote tumor cell survival, and elevated MIF protein correlates with tumor aggressiveness and poor prognosis. However, the molecular mechanism facilitating MIF stabilization in tumors is not understood. We show that the tumor-activated HSP90 chaperone complex protects MIF from degradation. Pharmacological inhibition of HSP90 activity, or siRNA-mediated knockdown of HSP90 or HDAC6, destabilizes MIF in a variety of human cancer cells. The HSP90-associated E3 ubiquitin ligase CHIP mediates the ensuing proteasome-dependent MIF degradation. Cancer cells contain constitutive endogenous MIF-HSP90 complexes. siRNA-mediated MIF knockdown inhibits proliferation and triggers apoptosis of cultured human cancer cells, whereas HSP90 inhibitor-induced apoptosis is overridden by ectopic MIF expression. In the ErbB2 transgenic model of human HER2-positive breast cancer, genetic ablation of MIF delays tumor progression and prolongs overall survival of mice. Systemic treatment with the HSP90 inhibitor 17AAG reduces MIF expression and blocks growth of MIF-expressing, but not MIF-deficient, tumors. Together, these findings identify MIF as a novel HSP90 client and suggest that HSP90 inhibitors inhibit ErbB2-driven breast tumor growth at least in part by destabilizing MIF.
authors.affiliation: Department of Molecular Oncology, Göttingen Center of Molecular Biosciences, University of Göttingen, 37077 Göttingen, Germany.
authors.forename: Ramona
authors.initials: R
authors.lastname: Schulz
authors.forename: Natalia D
authors.initials: ND
authors.lastname: Marchenko
authors.forename: Lena
authors.initials: L
authors.lastname: Holembowski
authors.forename: Günter
authors.initials: G
authors.lastname: Fingerle-Rowson
authors.forename: Marina
authors.initials: M
authors.lastname: Pesic
authors.forename: Lars
authors.initials: L
authors.lastname: Zender
authors.forename: Matthias
authors.initials: M
authors.lastname: Dobbelstein
authors.forename: Ute M
authors.initials: UM
authors.lastname: Moll
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D016227:Benzoquinones / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D017931:DNA Primers / Q000235:genetics; D003720:Densitometry; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000378:metabolism*; D055550:Protein Stability; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018719:Erb-b2 Receptor Tyrosine Kinases; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D016227:Benzoquinones; D017931:DNA Primers; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D008263:Macrophage Migration-Inhibitory Factors; D046912:Multiprotein Complexes; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D044767:Ubiquitin-Protein Ligases; C112765:tanespimycin; C467728:STUB1 protein, human; C524056:Erbb2 protein, mouse