The Role of MIF in cancer in vivo
Final Report 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 inhibitorinduced 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-de!cient, tumors. Together, these !ndings 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. Constitutively stabilized HSP90 clients are crucial for tumor survival and progression. HSP90 inhibitors represent a promising new class of drugs, despite - or perhaps because of - their pleiotropic effects of destabilizing a variety of critical oncoproteins. We identified MIF as an essential HSP90 client in the mouse model of Her2-overexpressing breast cancer. On the basis of these new findings, we asked whether MIF levels correlate with a specific breast cancer subtype. First results with human patient samples showed a correlation between ErbB2 expression and elevated MIF levels. To further address this point we started an analysis in ErbB2 overexpressing human breast cancer cell lines and their impact on MIF level. Preliminary results indicate that pharmacologic ErbB2 inhibition reduces MIF levels via a ErbB2-Akt-Hsf- 1-Hsp90 pathway. First pharmacological studies with our mouse ErBB2 breast cancer model confirm this in vitro finding. Lapatinib/Tyverb-treated ErbB2 mice show a reduction in tumor growth, a downregulation of activated phosphoHsf-1 and heat-shock proteins and reduced MIF levels. Our studies identify HSP90-stabilized MIF as an important promoter of tumor progression. Moreover, in vivo they show that reduction of MIF, rather than ErbB2 and Akt, by pharmacological HSP90 inhibition is the decisive determinant in inhibiting growth of ErbB2-driven breast cancers. Our direction is to determine in which human breast cancer subtypes MIF is relevant and to inhibit its tumor-promoting function by improved Hsp90 inhibitors.
Publications
- HSP90 inhibitor antagonizing MIF: The specifics of pleiotropic cancer drug candidates. OncoImmunology 2012 Dec 1:9, 1–2
Schulz R, Dobbelstein M and Moll UM
- Inhibiting the HSP90 chaperone destabilizes macrophage migration inhibitory factor and thereby inhibits breast tumor progression. J Exp Med. 2012 Feb 13; 209(2):275-89. Epub 2012 Jan 23
Schulz R, Marchenko ND, Holembowski L, Fingerle-Rowson G, Pesic M, Zender L, Dobbelstein M and Moll UM
(See online at https://doi.org/10.1084/jem.20111117)
