TY - JOUR
T1 - FGF Trapping Inhibits Multiple Myeloma Growth through c-Myc Degradation-Induced Mitochondrial Oxidative Stress
AU - Ronca, Roberto
AU - Ghedini, Gaia C
AU - Maccarinelli, Federica
AU - Sacco, Antonio
AU - Locatelli, Silvia L
AU - Foglio, Eleonora
AU - Taranto, Sara
AU - Grillo, Elisabetta
AU - Matarazzo, Sara
AU - Castelli, Riccardo
AU - Paganini, Giuseppe
AU - Desantis, Vanessa
AU - Cattane, Nadia
AU - Cattaneo, Annamaria
AU - Mor, Marco
AU - Carlo-Stella, Carmelo
AU - Belotti, Angelo
AU - Roccaro, Aldo M
AU - Presta, Marco
AU - Giacomini, Arianna
N1 - ©2020 American Association for Cancer Research.
PY - 2020/6/1
Y1 - 2020/6/1
N2 - 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.
AB - 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.
KW - Animals
KW - Apoptosis/drug effects
KW - Cell Line, Tumor
KW - Cholesterol/analogs & derivatives
KW - Female
KW - Fibroblast Growth Factors/antagonists & inhibitors
KW - Humans
KW - Mice
KW - Mice, Inbred NOD
KW - Mice, SCID
KW - Mitochondria/drug effects
KW - Multiple Myeloma/drug therapy
KW - Oxidative Stress/physiology
KW - Proto-Oncogene Proteins c-myc/metabolism
KW - Random Allocation
KW - Receptors, Fibroblast Growth Factor/antagonists & inhibitors
KW - Signal Transduction/drug effects
KW - Xenograft Model Antitumor Assays
KW - Zebrafish
U2 - 10.1158/0008-5472.CAN-19-2714
DO - 10.1158/0008-5472.CAN-19-2714
M3 - Article
C2 - 32094301
VL - 80
SP - 2340
EP - 2354
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0008-5472
IS - 11
ER -