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

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


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. ©2016 AACR.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Biomarkers, Tumor / metabolism*
  • Blotting, Western
  • Case-Control Studies
  • Cell Cycle
  • Cell Proliferation
  • Female
  • Follow-Up Studies
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Immunoenzyme Techniques
  • Macrophages / metabolism
  • Macrophages / pathology*
  • Male
  • Melanoma / metabolism
  • Melanoma / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Nude
  • Monoamine Oxidase / metabolism*
  • Neoplasm Staging
  • Prognosis
  • Proto-Oncogene Proteins c-akt / metabolism
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction
  • Survival Rate
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Biomarkers, Tumor
  • STAT3 Transcription Factor
  • Monoamine Oxidase
  • renalase
  • Proto-Oncogene Proteins c-akt
  • p38 Mitogen-Activated Protein Kinases