FGF Trapping Inhibits Multiple Myeloma Growth through c-Myc Degradation-Induced Mitochondrial Oxidative Stress

Roberto Ronca, Gaia C Ghedini, Federica Maccarinelli, Antonio Sacco, Silvia L Locatelli, Eleonora Foglio, Sara Taranto, Elisabetta Grillo, Sara Matarazzo, Riccardo Castelli, Giuseppe Paganini, Vanessa Desantis, Nadia Cattane, Annamaria Cattaneo, Marco Mor, Carmelo Carlo-Stella, Angelo Belotti, Aldo M Roccaro, Marco Presta, Arianna Giacomini

Research output: Contribution to journalArticlepeer-review

Abstract

Multiple myeloma, the second most common hematologic malignancy, frequently relapses because of chemotherapeutic resistance. Fibroblast growth factors (FGF) act as proangiogenic and mitogenic cytokines in multiple myeloma. Here, we demonstrate that the autocrine FGF/FGFR axis is essential for multiple myeloma cell survival and progression by protecting multiple myeloma cells from oxidative stress-induced apoptosis. In keeping with the hypothesis that the intracellular redox status can be a target for cancer therapy, FGF/FGFR blockade by FGF trapping or tyrosine kinase inhibitor impaired the growth and dissemination of multiple myeloma cells by inducing mitochondrial oxidative stress, DNA damage, and apoptotic cell death that were prevented by the antioxidant vitamin E or mitochondrial catalase overexpression. In addition, mitochondrial oxidative stress occurred as a consequence of proteasomal degradation of the c-Myc oncoprotein that led to glutathione depletion. Accordingly, expression of a proteasome-nondegradable c-Myc protein mutant was sufficient to avoid glutathione depletion and rescue the proapoptotic effects due to FGF blockade. These findings were confirmed on bortezomib-resistant multiple myeloma cells as well as on bone marrow-derived primary multiple myeloma cells from newly diagnosed and relapsed/refractory patients, including plasma cells bearing the t(4;14) translocation obtained from patients with high-risk multiple myeloma. Altogether, these findings dissect the mechanism by which the FGF/FGFR system plays a nonredundant role in multiple myeloma cell survival and disease progression, and indicate that FGF targeting may represent a therapeutic approach for patients with multiple myeloma with poor prognosis and advanced disease stage. SIGNIFICANCE: This study provides new insights into the mechanisms by which FGF antagonists promote multiple myeloma cell death. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/11/2340/F1.large.jpg.

Original languageEnglish
Pages (from-to)2340-2354
Number of pages15
JournalCancer Research
Volume80
Issue number11
DOIs
Publication statusPublished - Jun 1 2020

Keywords

  • Animals
  • Apoptosis/drug effects
  • Cell Line, Tumor
  • Cholesterol/analogs & derivatives
  • Female
  • Fibroblast Growth Factors/antagonists & inhibitors
  • Humans
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Mitochondria/drug effects
  • Multiple Myeloma/drug therapy
  • Oxidative Stress/physiology
  • Proto-Oncogene Proteins c-myc/metabolism
  • Random Allocation
  • Receptors, Fibroblast Growth Factor/antagonists & inhibitors
  • Signal Transduction/drug effects
  • Xenograft Model Antitumor Assays
  • Zebrafish

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