Editors' ChoiceCancer

EGFR deploys its own defense

See allHide authors and affiliations

Sci. Signal.  13 Oct 2015:
Vol. 8, Issue 398, pp. ec289
DOI: 10.1126/scisignal.aad6019

The epidermal growth factor receptor (EGFR) is activated in many cancers and promotes tumor growth. Macrophage migration inhibitory factor (MIF), an immunostimulatory cytokine, is also abnormally abundant in several cancer cell types, but its correlation with tumor progression is debated. Zheng et al. found that a posttranslationally modified form of MIF bound to and inhibited ligand-induced activation of EGFR and that cancers with activating mutations in EGFR promoted the degradation of MIF. Overexpressing MIF in epidermoid A431 cancer cells or adding MIF immunoprecipitated from human cells to the medium inhibited EGF-induced phosphorylation of EGFR and its downstream signaling mediators. Binding assays revealed that MIF isolated from human cells, but not that isolated from bacteria, bound to EGFR directly and inhibited its interaction with EGF. Mass spectrometry revealed that MIF purified from human cells was modified by O-linked β-N-acetylglucosamine (O-GlcNAc). In contrast to wild-type MIF, an O-GlcNAcylation-deficient MIF mutant did not bind to EGFR and did not block EGF from binding to EGFR or from inducing migration in cultured A431 or U87 cells. Likewise, the growth of intracranial xenografts derived from U87 cells expressing wild-type was substantially less than those derived from cells expressing mutant MIF. However, migration in culture and intracranial xenograft growth were unaffected by overexpression of wild-type MIF in U87 cells which express the constitutively active EGFRvIII mutant. Expression of EGFRvIII or prolonged EGF treatment decreased the amount of MIF present in the medium (without affecting intracellular MIF abundance) while increasing that of matrix metalloprotease 13 (MMP-13). Both MIF degradation and MMP-13 secretion in response to EGF was blocked by pretreating cells with a pharmacological EGFR inhibitor. Pretreating the cells with a pharmacological inhibitor of MMP-13 or a MMP13-targeted short hairpin RNA blocked both the degradation of extracellular MIF and the phosphorylation of EGFR in the presence of EGF. The findings suggest that cancer cells bearing activating mutations in EGFR promote the destruction of the inhibitor MIF in the tumor microenvironment and that targeting MMP-13 might be a new therapeutic strategy to block EGFRvIII-positive tumor growth.

Y. Zheng, X. Li, X. Qian, Y. Wang, J.-H. Lee, Y. Xia, D. H. Hawke, G. Zhang, J. Lyu, Z. Lu, Secreted and O-GlcNAcylated MIF binds to the human EGF receptor and inhibits its activation. Nat. Cell Biol. 17, 1348–1355 (2015). [PubMed]