title: Renalase Expression by Melanoma and Tumor-Associated Macrophages Promotes Tumor Growth through a STAT3-Mediated Mechanism.
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. ©2016 AACR.
authors.affiliation: Department of Medicine, Yale University, New Haven, Connecticut. Yale School of Medicine, Yale University, New Haven, Connecticut. University of Connecticut, Farmington, Connecticut.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Hollander
authors.affiliation: Department of Medicine, Yale University, New Haven, Connecticut. Yale School of Medicine, Yale University, New Haven, Connecticut.
authors.forename: Xiaojia
authors.initials: X
authors.lastname: Guo
authors.affiliation: 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.
authors.forename: Heino
authors.initials: H
authors.lastname: Velazquez
authors.affiliation: Department of Medicine, Yale University, New Haven, Connecticut. VA Connecticut Health Care System, Yale University, New Haven, Connecticut.
authors.forename: John
authors.initials: J
authors.lastname: Chang
authors.affiliation: 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.
authors.forename: Robert
authors.initials: R
authors.lastname: Safirstein
authors.affiliation: Department of Medical Oncology, Yale University, New Haven, Connecticut. Yale School of Medicine, Yale University, New Haven, Connecticut.
authors.forename: Harriet
authors.initials: H
authors.lastname: Kluger
authors.affiliation: 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.
authors.forename: Charles
authors.initials: C
authors.lastname: Cha
authors.affiliation: 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.
authors.forename: Gary V
authors.initials: GV
authors.lastname: Desir
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D016022:Case-Control Studies; D002453:Cell Cycle; D049109:Cell Proliferation; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008995:Monoamine Oxidase / Q000378:metabolism*; D009367:Neoplasm Staging; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D050796:STAT3 Transcription Factor; D008995:Monoamine Oxidase; C521557:renalase; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases