Abstract
Background: DDT is a novel member of the MIF cytokine family with overlapping functions. Results: DDT is a direct HIF target gene that is expressed widely in renal carcinoma and contributes to tumorigenesis. Conclusion: DDT has greater tumor-promoting properties than MIF and may compensate for MIF inhibition. Significance: Efforts to inhibit MIF signaling in cancer need to target DDT as well. Clear cell renal cell carcinomas (ccRCCs) are characterized by biallelic loss of the von Hippel-Lindau tumor suppressor and subsequent constitutive activation of the hypoxia-inducible factors, whose transcriptional programs dictate major phenotypic attributes of kidney tumors.Werecently described a role for the macrophage migration inhibitory factor (MIF) in ccRCC as an autocrine-signaling molecule with elevated expression in tumor tissues and in the circulation of patients that has potent tumor cell survival effects. MIF is a pleiotropic cytokine implicated in a variety of diseases and cancers and is the target of both small molecule and antibody-based therapies currently in clinical trials. Recent work by others has described D-dopachrome tautomerase (DDT) as a functional homologue of MIF with a similar genomic structure and expression patterns. Thus, we sought to determine a role for DDT in renal cancer. We find that DDT expression mirrors MIF expression in ccRCC tumor sections with high correlation and that, mechanistically, DDT is a novel hypoxia-inducible gene and direct target of HIF1+ and HIF2+. Functionally,DDTandMIFdemonstrate a significant overlap in controlling cell survival, tumor formation, and tumor and endothelial cell migration. However, DDT inhibition consistently displayed more severe effects on most phenotypes. Accordingly, although dual inhibition of DDT and MIF demonstrated additive effects in vitro, DDT plays a dominant role in tumor growth in vivo. Together, our findings identify DDT as a functionally redundant but more potent cytokine to MIF in cancer and suggest that current attempts to inhibit MIF signaling may fail because of DDT compensation.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 3713-3723 |
| Number of pages | 11 |
| Journal | Journal of Biological Chemistry |
| Volume | 289 |
| Issue number | 6 |
| DOIs | |
| State | Published - Feb 7 2014 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Biochemistry
- Cell Biology
- Molecular Biology
Cite this
Dysregulated D-dopachrome Tautomerase, a Hypoxiainducible Factor-dependent Gene, cooperates with Macrophage migration inhibitory factor in Renal Tumorigenesis. / Pasupuleti, Vinay; Du, Weinan; Gupta, Yashi; Yeh, I. Ju; Montano, Monica; Magi-Galuzzi, Cristina; Welford, Scott.
In: Journal of Biological Chemistry, Vol. 289, No. 6, 07.02.2014, p. 3713-3723.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Dysregulated D-dopachrome Tautomerase, a Hypoxiainducible Factor-dependent Gene, cooperates with Macrophage migration inhibitory factor in Renal Tumorigenesis
AU - Pasupuleti, Vinay
AU - Du, Weinan
AU - Gupta, Yashi
AU - Yeh, I. Ju
AU - Montano, Monica
AU - Magi-Galuzzi, Cristina
AU - Welford, Scott
PY - 2014/2/7
Y1 - 2014/2/7
N2 - Background: DDT is a novel member of the MIF cytokine family with overlapping functions. Results: DDT is a direct HIF target gene that is expressed widely in renal carcinoma and contributes to tumorigenesis. Conclusion: DDT has greater tumor-promoting properties than MIF and may compensate for MIF inhibition. Significance: Efforts to inhibit MIF signaling in cancer need to target DDT as well. Clear cell renal cell carcinomas (ccRCCs) are characterized by biallelic loss of the von Hippel-Lindau tumor suppressor and subsequent constitutive activation of the hypoxia-inducible factors, whose transcriptional programs dictate major phenotypic attributes of kidney tumors.Werecently described a role for the macrophage migration inhibitory factor (MIF) in ccRCC as an autocrine-signaling molecule with elevated expression in tumor tissues and in the circulation of patients that has potent tumor cell survival effects. MIF is a pleiotropic cytokine implicated in a variety of diseases and cancers and is the target of both small molecule and antibody-based therapies currently in clinical trials. Recent work by others has described D-dopachrome tautomerase (DDT) as a functional homologue of MIF with a similar genomic structure and expression patterns. Thus, we sought to determine a role for DDT in renal cancer. We find that DDT expression mirrors MIF expression in ccRCC tumor sections with high correlation and that, mechanistically, DDT is a novel hypoxia-inducible gene and direct target of HIF1+ and HIF2+. Functionally,DDTandMIFdemonstrate a significant overlap in controlling cell survival, tumor formation, and tumor and endothelial cell migration. However, DDT inhibition consistently displayed more severe effects on most phenotypes. Accordingly, although dual inhibition of DDT and MIF demonstrated additive effects in vitro, DDT plays a dominant role in tumor growth in vivo. Together, our findings identify DDT as a functionally redundant but more potent cytokine to MIF in cancer and suggest that current attempts to inhibit MIF signaling may fail because of DDT compensation.
AB - Background: DDT is a novel member of the MIF cytokine family with overlapping functions. Results: DDT is a direct HIF target gene that is expressed widely in renal carcinoma and contributes to tumorigenesis. Conclusion: DDT has greater tumor-promoting properties than MIF and may compensate for MIF inhibition. Significance: Efforts to inhibit MIF signaling in cancer need to target DDT as well. Clear cell renal cell carcinomas (ccRCCs) are characterized by biallelic loss of the von Hippel-Lindau tumor suppressor and subsequent constitutive activation of the hypoxia-inducible factors, whose transcriptional programs dictate major phenotypic attributes of kidney tumors.Werecently described a role for the macrophage migration inhibitory factor (MIF) in ccRCC as an autocrine-signaling molecule with elevated expression in tumor tissues and in the circulation of patients that has potent tumor cell survival effects. MIF is a pleiotropic cytokine implicated in a variety of diseases and cancers and is the target of both small molecule and antibody-based therapies currently in clinical trials. Recent work by others has described D-dopachrome tautomerase (DDT) as a functional homologue of MIF with a similar genomic structure and expression patterns. Thus, we sought to determine a role for DDT in renal cancer. We find that DDT expression mirrors MIF expression in ccRCC tumor sections with high correlation and that, mechanistically, DDT is a novel hypoxia-inducible gene and direct target of HIF1+ and HIF2+. Functionally,DDTandMIFdemonstrate a significant overlap in controlling cell survival, tumor formation, and tumor and endothelial cell migration. However, DDT inhibition consistently displayed more severe effects on most phenotypes. Accordingly, although dual inhibition of DDT and MIF demonstrated additive effects in vitro, DDT plays a dominant role in tumor growth in vivo. Together, our findings identify DDT as a functionally redundant but more potent cytokine to MIF in cancer and suggest that current attempts to inhibit MIF signaling may fail because of DDT compensation.
UR - http://www.scopus.com/inward/record.url?scp=84893670415&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84893670415&partnerID=8YFLogxK
U2 - 10.1074/jbc.M113.500694
DO - 10.1074/jbc.M113.500694
M3 - Article
C2 - 24356968
AN - SCOPUS:84893670415
VL - 289
SP - 3713
EP - 3723
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 6
ER -