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Cancer Res. 2016 Jul 1;76(13):3884-94. doi: 10.1158/0008-5472.CAN-15-1524. Epub 2016 May 9.

Renalase Expression by Melanoma and Tumor-Associated Macrophages Promotes Tumor Growth through a STAT3-Mediated Mechanism.

Author information

1
Department of Medicine, Yale University, New Haven, Connecticut. Yale School of Medicine, Yale University, New Haven, Connecticut. University of Connecticut, Farmington, Connecticut.
2
Department of Medicine, Yale University, New Haven, Connecticut. Yale School of Medicine, Yale University, New Haven, Connecticut.
3
Department of Medicine, Yale University, New Haven, Connecticut. Yale School of Medicine, Yale University, New Haven, Connecticut. VA Connecticut Health Care System, Yale University, New Haven, Connecticut.
4
Department of Medicine, Yale University, New Haven, Connecticut. VA Connecticut Health Care System, Yale University, New Haven, Connecticut.
5
Department of Medical Oncology, Yale University, New Haven, Connecticut. Yale School of Medicine, Yale University, New Haven, Connecticut.
6
Yale School of Medicine, Yale University, New Haven, Connecticut. VA Connecticut Health Care System, Yale University, New Haven, Connecticut. Department of Surgery, Yale University, New Haven, Connecticut.
7
Department of Medicine, Yale University, New Haven, Connecticut. Yale School of Medicine, Yale University, New Haven, Connecticut. VA Connecticut Health Care System, Yale University, New Haven, Connecticut. gary.desir@yale.edu.

Abstract

To sustain their proliferation, cancer cells overcome negative-acting signals that restrain their growth and promote senescence and cell death. Renalase (RNLS) is a secreted flavoprotein that functions as a survival factor after ischemic and toxic injury, signaling through the plasma calcium channel PMCA4b to activate the PI3K/AKT and MAPK pathways. We show that RNLS expression is increased markedly in primary melanomas and CD163(+) tumor-associated macrophages (TAM). In clinical specimens, RNLS expression in the tumor correlated inversely with disease-specific survival, suggesting a pathogenic role for RNLS. Attenuation of RNLS by RNAi, blocking antibodies, or an RNLS-derived inhibitory peptide decreased melanoma cell survival, and anti-RNLS therapy blocked tumor growth in vivo in murine xenograft assays. Mechanistic investigations showed that increased apoptosis in tumor cells was temporally related to p38 MAPK-mediated Bax activation and that increased cell growth arrest was associated with elevated expression of the cell-cycle inhibitor p21. Overall, our results established a role for the secreted flavoprotein RNLS in promoting melanoma cell growth and CD163(+) TAM in the tumor microenvironment, with potential therapeutic implications for the management of melanoma. Cancer Res; 76(13); 3884-94.

PMID:
27197188
PMCID:
PMC5031238
DOI:
10.1158/0008-5472.CAN-15-1524
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

G Desir is a named inventor on several issued patents related to the discovery and therapeutic use of renalase. Renalase is licensed to Bessor Pharma, and G Desir holds an equity position in Bessor and its subsidiary Personal Therapeutics.

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