Iron regulates myeloma cell/macrophage interaction and drives resistance to bortezomib

Camiolo, G., Barbato, A., Giallongo, C., Vicario, N., Romano, A., Parrinello, N.L., Parenti, R., Sandoval, J.C., García-Moreno, D., Lazzarino, G., Avola, R., Palumbo, G.A., Mulero, V., Li Volti, G., Tibullo, D., Di Raimondo, F.
Redox Biology   36: 101611 (Journal)
Registered Authors
Mulero, Victor
Iron, Monocyte, Multiple myeloma, Zebrafish
MeSH Terms
  • Animals
  • Antineoplastic Agents*/pharmacology
  • Apoptosis
  • Bortezomib/pharmacology
  • Carrier Proteins
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • Extracellular Matrix Proteins
  • Glycoproteins/pharmacology
  • Glycoproteins/therapeutic use
  • Humans
  • Iron/pharmacology
  • Macrophages
  • Multiple Myeloma*/drug therapy
  • Tumor Microenvironment
  • Zebrafish
32863212 Full text @ Redox Biol.
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.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes