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

Camiolo, Giuseppina; Barbato, Alessandro; Giallongo, Cesarina; Vicario, Nunzio; Romano, Alessandra; Parrinello, Nunziatina Laura; Parenti, Rosalba; Sandoval, Joaquín Cantón; García‐Moreno, Diana; Lazzarino, Giacomo; Avola, Roberto; Palumbo, Giuseppe A.; Mulero, Victoriano; Volti, Giovanni Li; Tibullo, Daniele; Raimondo, Francesco Di

doi:10.1016/j.redox.2020.101611

Cited by 38 publications

(39 citation statements)

References 58 publications

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“…Bioenergetics changes, associated to increased mitochondrial biomass and function, can be elicited as part of the adaptive response to treatment (135)(136)(137)(138). In vitro, human MM cell lines resistant to bortezomib or dexamethasone have higher concentrations of ATP, NADH/NADPH ratio, associated to hyperpolarization of mitochondrial membrane leading to impaired drug response (137,139).…”

Section: Mitochondrial Fitness Mediates Resistance To Bortezomib In Mmentioning

confidence: 99%

“…MM can intake iron to increase their scavenger antioxidant-related genes and mitochondrial mass. Iron trafficking, by modifying energetic metabolism of cancer cells and impairing inflammatory status of macrophages in the microenvironment, is a critical regulator to reshape the MM tumor niche ( 135 ). However, to make the picture more complex, MM cell lines are characterized by distinct ferritin levels, which directly correlate with bortezomib resistance and pre-treatment with ferric ammonium citrate (FAC) decreased bortezomib sensitivity in vitro ( 135 ).…”

Section: Mitochondrial Fitness Mediates Resistance To Bortezomib In Mmentioning

confidence: 99%

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Mitochondrial Bioenergetics at the Onset of Drug Resistance in Hematological Malignancies: An Overview

et al. 2020

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The combined derangements in mitochondria network, function and dynamics can affect metabolism and ATP production, redox homeostasis and apoptosis triggering, contributing to cancer development in many different complex ways. In hematological malignancies, there is a strong relationship between cellular metabolism, mitochondrial bioenergetics, interconnections with supportive microenvironment and drug resistance. Lymphoma and chronic lymphocytic leukemia cells, e.g., adapt to intrinsic oxidative stress by increasing mitochondrial biogenesis. In other hematological disorders such as myeloma, on the contrary, bioenergetics changes, associated to increased mitochondrial fitness, derive from the adaptive response to drug-induced stress. In the bone marrow niche, a reverse Warburg effect has been recently described, consisting in metabolic changes occurring in stromal cells in the attempt to metabolically support adjacent cancer cells. Moreover, a physiological dynamic, based on mitochondria transfer, between tumor cells and their supporting stromal microenvironment has been described to sustain oxidative stress associated to proteostasis maintenance in multiple myeloma and leukemia. Increased mitochondrial biogenesis of tumor cells associated to acquisition of new mitochondria transferred by mesenchymal stromal cells results in augmented ATP production through increased oxidative phosphorylation (OX-PHOS), higher drug resistance, and resurgence after treatment. Accordingly, targeting mitochondrial biogenesis, electron transfer, mitochondrial DNA replication, or mitochondrial fatty acid transport increases therapy efficacy. In this review, we summarize selected examples of the mitochondrial derangements in hematological malignancies, which provide metabolic adaptation and apoptosis resistance, also supported by the crosstalk with tumor microenvironment. This field promises a rational design to improve target-therapy including the metabolic phenotype.

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Section: Mitochondrial Fitness Mediates Resistance To Bortezomib In Mmentioning

confidence: 99%

Section: Mitochondrial Fitness Mediates Resistance To Bortezomib In Mmentioning

confidence: 99%

Mitochondrial Bioenergetics at the Onset of Drug Resistance in Hematological Malignancies: An Overview

et al. 2020

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“…Additionally, M2 macrophages stimulate MCF-7 breast cancer cell growth and migration by an iron-dependent mechanism ( 42 ). Coculture with iron-loaded monocytes recapitulates the effects of iron treatment on rendering myeloma cells resistance to bortezomib ( 43 ).…”

Section: Iron Levels In the Tme Are Regulated By Innate Immune Cellsmentioning

confidence: 99%

Iron Metabolism in the Tumor Microenvironment: Contributions of Innate Immune Cells

Liang¹,

Ferrara

2021

Front. Immunol.

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Cells of the innate immune system are a major component of the tumor microenvironment. They play complex and multifaceted roles in the regulation of cancer initiation, growth, metastasis and responses to therapeutics. Innate immune cells like neutrophils and macrophages are recruited to cancerous tissues by chemotactic molecules released by cancer cells and cancer-associated stromal cells. Once they reach the tumor, they can be instructed by a network of proteins, nucleic acids and metabolites to exert protumoral or antitumoral functions. Altered iron metabolism is a feature of cancer. Epidemiological studies suggest that increased presence of iron and/or iron binding proteins is associated with increased risks of cancer development. It has been shown that iron metabolism is involved in shaping the immune landscapes in inflammatory/infectious diseases and cancer-associated inflammation. In this article, we will dissect the contribution of macrophages and neutrophils to dysregulated iron metabolism in malignant cells and its impact on cancer growth and metastasis. The mechanisms involved in regulating the actions of macrophages and neutrophils will also be discussed. Moreover, we will examine the effects of iron metabolism on the phenotypes of innate immune cells. Both iron chelating and overloading agents are being explored in cancer treatment. This review highlights alternative strategies for management of iron content in cancer cells by targeting the iron donation and modulation properties of macrophages and neutrophils in the tumor microenvironment.

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“…In multiple myeloma (MM), increased iron uptake and intracellular levels have been demonstrated to promote cell growth. Experiments in myeloma cell lines have shown that the increased cellular iron content induces ROS increase, which in turn stimulates an adaptive response mediated by the activation of the redox regulating genes and mitochondrial biogenesis and fitness [18]. The above mechanisms have also been proposed to be of relevance in the development of treatment resistance.…”

Section: Metabolic Changes In Hematologic Malignanciesmentioning

confidence: 99%

From the (Epi)Genome to Metabolism and Vice Versa; Examples from Hematologic Malignancy

Karagianni

Giannouli

Voulgarelis

2021

IJMS

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Hematologic malignancies comprise a heterogeneous group of neoplasms arising from hematopoietic cells or their precursors and most commonly presenting as leukemias, lymphomas, and myelomas. Genetic analyses have uncovered recurrent mutations which initiate or accumulate in the course of malignant transformation, as they provide selective growth advantage to the cell. These include mutations in genes encoding transcription factors and epigenetic regulators of metabolic genes, as well as genes encoding key metabolic enzymes. The resulting alterations contribute to the extensive metabolic reprogramming characterizing the transformed cell, supporting its increased biosynthetic needs and allowing it to withstand the metabolic stress that arises as a consequence of increased metabolic rates and changes in its microenvironment. Interestingly, this cross-talk is bidirectional, as metabolites also signal back to the nucleus and, via their widespread effects on modulating epigenetic modifications, shape the chromatin landscape and the transcriptional programs of the cell. In this article, we provide an overview of the main metabolic changes and relevant genetic alterations that characterize malignant hematopoiesis and discuss how, in turn, metabolites regulate epigenetic events during this process. The aim is to illustrate the intricate interrelationship between the genome (and epigenome) and metabolism and its relevance to hematologic malignancy.

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

Cited by 38 publications

References 58 publications

Mitochondrial Bioenergetics at the Onset of Drug Resistance in Hematological Malignancies: An Overview

Mitochondrial Bioenergetics at the Onset of Drug Resistance in Hematological Malignancies: An Overview

Iron Metabolism in the Tumor Microenvironment: Contributions of Innate Immune Cells

From the (Epi)Genome to Metabolism and Vice Versa; Examples from Hematologic Malignancy

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