Inhibition of TLR4 Signaling Affects Mitochondrial Fitness and Overcomes Bortezomib Resistance in Myeloma Plasma Cells

Giallongo, Cesarina; Tibullo, Daniele; Puglisi, Fabrizio; Barbato, Alessandro; Vicario, Nunzio; Cambria, Daniela; Parrinello, Nunziatina Laura; Romano, Alessandra; Conticello, Concetta; Forte, Stefano; Parenti, Rosalba; Amorini, Angela Maria; Lazzarino, Giuseppe; Volti, Giovanni Li; Palumbo, Giuseppe A.; Raimondo, Francesco Di

doi:10.3390/cancers12081999

Cited by 29 publications

(28 citation statements)

References 55 publications

(73 reference statements)

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“…A membrane potential probe, 3,3′-diethyloxacarbocyanine iodide (DiOC2(3)), (Thermo Fisher Scientific, Milan, Italy), was used to evaluate the mitochondrial membrane potential [ 37 , 38 , 39 ]. Cells were incubated with 10 μM DiOC2(3) for 30 min at 37 °C, washed twice, resuspended in PBS and analyzed by flow cytometry.…”

Section: Methodsmentioning

confidence: 99%

Neuroprotective Role of α-Lipoic Acid in Iron-Overload-Mediated Toxicity and Inflammation in In Vitro and In Vivo Models

et al. 2022

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Hemoglobin and iron overload is considered the major contributor to intracerebral hemorrhage (ICH)-induced brain injury. Accumulation of iron in the brain leads to microglia activation, inflammation and cell loss. Current available treatments for iron overload-mediated disorders are characterized by severe adverse effects, making such conditions an unmet clinical need. We assessed the potential of α-lipoic acid (ALA) as an iron chelator, antioxidant and anti-inflammatory agent in both in vitro and in vivo models of iron overload. ALA was found to revert iron-overload-induced toxicity in HMC3 microglia cell line, preventing cell apoptosis, reactive oxygen species generation and reducing glutathione depletion. Furthermore, ALA regulated gene expression of iron-related markers and inflammatory cytokines, such as IL-6, IL-1β and TNF. Iron toxicity also affects mitochondria fitness and biogenesis, impairments which were prevented by ALA pre-treatment in vitro. Immunocytochemistry assay showed that, although iron treatment caused inflammatory activation of microglia, ALA treatment resulted in increased ARG1 expression, suggesting it promoted an anti-inflammatory phenotype. We also assessed the effects of ALA in an in vivo zebrafish model of iron overload, showing that ALA treatment was able to reduce iron accumulation in the brain and reduced iron-mediated oxidative stress and inflammation. Our data support ALA as a novel approach for iron-overload-induced brain damage.

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Section: Methodsmentioning

confidence: 99%

Neuroprotective Role of α-Lipoic Acid in Iron-Overload-Mediated Toxicity and Inflammation in In Vitro and In Vivo Models

et al. 2022

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“…Our group has recently disclosed that TLR4 acts as a mitochondria protective factor against bortezomib-induced mitochondria damage and apoptosis ( 144 ). Targeting TLR4 signaling in bortezomib resistant cells damages mitochondrial fitness and increases mitophagy leading to apoptosis.…”

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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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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“…Consistent with the results in vitro , LPS caused the increased mitophagy proteins in heart tissue homogenates of LPS-treated mice, which was restored by Bazedoxifene treatment ( Figure 6J ; Supplementary Figures S3D–F ). It is well-known that mitochondrial dysfunction contributed to oxidative stress ( 19 , 20 ). Next, we checked the level of intracellular ROS using the fluorescent dye H2DCFDA in H9c2 cells.…”

Section: Resultsmentioning

confidence: 99%

IL-6/STAT3 Signaling Promotes Cardiac Dysfunction by Upregulating FUNDC1-Dependent Mitochondria-Associated Endoplasmic Reticulum Membranes Formation in Sepsis Mice

Jiang

Peng

Shi

et al. 2022

Front. Cardiovasc. Med.

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AimsCytokine storm is closely related to the initiation and progression of sepsis, and the level of IL-6 is positively correlated with mortality and organ dysfunction. Sepsis-induced myocardial dysfunction (SIMD) is one of the major complications. However, the role of the IL-6/STAT3 signaling in the SIMD remains unclear.Methods and ResultsSeptic mice were induced by intraperitoneal injection of LPS (10 mg/kg). Echocardiography, cytokines detection, and histologic examination showed that sepsis mice developed cardiac systolic and diastolic dysfunction, increase of inflammatory cytokines in serum, activated STAT3 and TLR4/NFκB pathway in heart, and raised myocardial apoptosis, which were attenuated by IL-6/STAT3 inhibitor, Bazedoxifene. In vitro, we found that LPS decreased cell viability in a concentration-dependent manner and activated STAT3. Western blot and immunofluorescence results indicated that STAT3 phosphorylation induced by LPS was inhibited by Bazedoxifene. Bazedoxifene also suppressed LPS-induced IL-6 transcription. sIL-6R caused LPS-induced p-STAT3 firstly decreased and then significantly increased. More importantly, we found STAT3-knockdown suppressed LPS-induced expression of FUNDC1, a protein located in mitochondria-associated endoplasmic reticulum membranes (MAMs). Overexpression of STAT3 led to an increase in FUNDC1 expression. Dual-luciferase reporter assay was used to confirm that STAT3 was a potential transcription factor for FUNDC1. Moreover, we showed that LPS increased MAMs formation and intracellular Ca2+ levels, enhanced the expression of Cav1.2 and RyR2, decreased mitochondrial membrane potential and intracellular ATP levels, and promoted mitochondrial fragmentation, the expression of mitophagy proteins and ROS production in H9c2 cells, which were reversed by knockdown of FUNDC1 and IL-6/STAT3 inhibitor including Bazedoxifene and Stattic.ConclusionsIL-6/STAT3 pathway plays a key role in LPS-induced myocardial dysfunction, through regulating the FUNDC1-associated MAMs formation and interfering the function of ER and mitochondria. IL-6/STAT3/FUNDC1 signaling could be a new therapeutic target for SIMD.

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Inhibition of TLR4 Signaling Affects Mitochondrial Fitness and Overcomes Bortezomib Resistance in Myeloma Plasma Cells

Cited by 29 publications

References 55 publications

Neuroprotective Role of α-Lipoic Acid in Iron-Overload-Mediated Toxicity and Inflammation in In Vitro and In Vivo Models

Neuroprotective Role of α-Lipoic Acid in Iron-Overload-Mediated Toxicity and Inflammation in In Vitro and In Vivo Models

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

IL-6/STAT3 Signaling Promotes Cardiac Dysfunction by Upregulating FUNDC1-Dependent Mitochondria-Associated Endoplasmic Reticulum Membranes Formation in Sepsis Mice

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