Iron regulates myeloma cell/macrophage interaction and drives resistance to bortezomib
Giuseppina Camiolo,
Alessandro Barbato,
Cesarina Giallongo,
Nunzio Vicario,
Alessandra Romano,
Nunziatina L. Parrinello,
Rosalba Parenti,
Joaquín Cantón Sandoval,
Diana García-Moreno,
Giacomo Lazzarino,
Roberto Avola,
Giuseppe A. Palumbo,
Victoriano Mulero,
Giovanni Li Volti,
Daniele Tibullo,
Francesco Di Raimondo
Affiliations
Giuseppina Camiolo
Section of Biochemistry, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123, Catania, Italy
Alessandro Barbato
Section of Hematology, Department of Medical and Surgical Specialties, A.O.U. Policlinico-OVE, University of Catania, 95125, Catania, Italy
Cesarina Giallongo
Section of Hematology, Department of Medical, Surgical Sciences and Advanced Technologies “G.F. Ingrassia”, A.O.U. Policlinico-OVE, University of Catania, 95125, Catania, Italy; Corresponding author.
Nunzio Vicario
Section of Physiology, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123, Catania, Italy
Alessandra Romano
Section of Hematology, Department of Medical and Surgical Specialties, A.O.U. Policlinico-OVE, University of Catania, 95125, Catania, Italy
Nunziatina L. Parrinello
Division of Hematology, A.O.U. Policlinico-OVE, University of Catania, 95122, Catania, Italy
Rosalba Parenti
Section of Physiology, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123, Catania, Italy
Joaquín Cantón Sandoval
Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de MurciaIMIB-Arrixaca, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Murcia, 30100, Spain
Diana García-Moreno
Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de MurciaIMIB-Arrixaca, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Murcia, 30100, Spain
Giacomo Lazzarino
UniCamillus - Saint Camillus International University of Health Sciences, Via di Sant’Alessandro 8, 00131, Rome, Italy
Roberto Avola
Section of Biochemistry, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123, Catania, Italy
Giuseppe A. Palumbo
Section of Hematology, Department of Medical, Surgical Sciences and Advanced Technologies “G.F. Ingrassia”, A.O.U. Policlinico-OVE, University of Catania, 95125, Catania, Italy
Victoriano Mulero
Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de MurciaIMIB-Arrixaca, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Murcia, 30100, Spain
Giovanni Li Volti
Section of Biochemistry, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123, Catania, Italy; Corresponding author.
Daniele Tibullo
Section of Biochemistry, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123, Catania, Italy
Francesco Di Raimondo
Section of Hematology, Department of Medical and Surgical Specialties, A.O.U. Policlinico-OVE, University of Catania, 95125, Catania, Italy
Iron plays a major role in multiple processes involved in cell homeostasis such as metabolism, respiration and DNA synthesis. Cancer cells exhibit pronounced iron retention as compared to healthy counterpart. This phenomenon also occurs in multiple myeloma (MM), a hematological malignancy characterized by terminally differentiated plasma cells (PCs), in which serum ferritin levels have been reported as a negative prognostic marker. The aim of current study is to evaluate the potential role of iron metabolism in promoting drug resistance in myeloma cancer cells with particular regard to the interactions between PCs and tumor-associated macrophages (TAMs) as a source of iron. Our data showed that myeloma cell lines are able to intake and accumulate iron and thus, increasing their scavenger antioxidant-related genes and mitochondrial mass. We further demonstrated that PCs pre-treated with ferric ammonium citrate (FAC) decreased bortezomib (BTZ)-induced apoptosis in vitro and successfully engrafted in zebrafish larvae treated with BTZ. Treating human macrophages with FAC, we observed a switch toward a M2-like phenotype associated with an increased expression of anti-inflammatory markers such as ARG1, suggesting the establishment of an iron-mediated immune suppressive tumor microenvironment favouring myeloma growth. Using mfap4:tomato mutant zebrafish larvae, we further confirmed the increase of PCs-monocytes interactions after FAC treatment which favour BTZ-resistance. Taken together our data support the hypothesis that targeting iron trafficking in myeloma microenvironment may represent a promising strategy to counteract a tumor-supporting milieu and drug resistance.
