PML at mitochondria-associated membranes governs a trimeric complex with NLRP3 and P2X7R that modulates the tumor immune microenvironment

Missiroli, Sonia; Perrone, Mariasole; Gafà, Roberta; Nicoli, F; Bonora, Massimo; Morciano, Giampaolo; Boncompagni, Caterina; Marchi, Saverio; Lebiedzińska-Arciszewska, Magdalena; Vezzani, Bianca; Lanza, Giovanni; Kricek, Franz; Borghi, Alessandro; Fiorica, Francesco; Ito, Keisuke; Wiêckowski, Mariusz R.; Virgilio, Francesco Di; Abelli, Luigi; Pinton, Paolo; Giorgi, Carlotta

doi:10.1038/s41418-022-01095-9

Cited by 21 publications

(17 citation statements)

References 39 publications

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“…NLRP3-dependent inflammation provides a more permissive environment for tumor proliferation. , In particular, NLRP3 activation and the subsequent formation of the NLRP3 inflammasome were recently shown to be involved in melanoma progression . Thus, we next evaluated the effect of NLRP3 inhibition in vivo in a mouse cancer model.…”

Section: Resultsmentioning

confidence: 99%

Novel Aryl Sulfonamide Derivatives as NLRP3 Inflammasome Inhibitors for the Potential Treatment of Cancer

et al. 2023

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The NLRP3 inflammasome is a critical component of innate immunity that senses diverse pathogen-and host-derived molecules. However, its aberrant activation has been associated with the pathogenesis of multiple diseases, including cancer. In this study, we designed and synthesized a series of aryl sulfonamide derivatives (ASDs) to inhibit the NLRP3 inflammasome. Among these, compounds 6c, 7n, and 10 specifically inhibited NLRP3 activation at nanomolar concentrations without affecting the activation of the NLRC4 and AIM2 inflammasomes. Furthermore, we demonstrated that these compounds reduce interleukin-1β (IL-1β) production in vivo and attenuate melanoma tumor growth. Moreover, metabolic stability in liver microsomes of 6c, 7n, and 10 was studied along with plasma exposure in mice of the most interesting compound 6c. Therefore, we generated potent NLRP3 inflammasome inhibitors, which can be considered in future medicinal chemistry and pharmacological studies aimed at developing a new therapeutic approach for NLRP3 inflammasome-driven cancer.

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Section: Resultsmentioning

confidence: 99%

Novel Aryl Sulfonamide Derivatives as NLRP3 Inflammasome Inhibitors for the Potential Treatment of Cancer

et al. 2023

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“…(2) The target processes of tumor cell metabolic reprogramming, such as the tricarboxylic acid cycle and electron transport chain, are carried out in mitochondria. (3) Signaling molecules associated with tumorigenesis, such as STAT3 [ 132 ], TERT [ 221 ], PML [ 222 ], p53 [ 223 ], and HSP60 [ 213 ], can also be found in mitochondria. (4) Mitochondria are connected to other subcellular organelles involved in regulating tumorigenesis, such as the nucleus [ 224 ] and endoplasmic reticulum (ER).…”

Section: Discussionmentioning

confidence: 99%

The Role of Oxidative Stress in Tumorigenesis and Progression

Li,

Deng,

Lei

et al. 2024

Cells

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Oxidative stress refers to the imbalance between the production of reactive oxygen species (ROS) and the endogenous antioxidant defense system. Its involvement in cell senescence, apoptosis, and series diseases has been demonstrated. Advances in carcinogenic research have revealed oxidative stress as a pivotal pathophysiological pathway in tumorigenesis and to be involved in lung cancer, glioma, hepatocellular carcinoma, leukemia, and so on. This review combs the effects of oxidative stress on tumorigenesis on each phase and cell fate determination, and three features are discussed. Oxidative stress takes part in the processes ranging from tumorigenesis to tumor death via series pathways and processes like mitochondrial stress, endoplasmic reticulum stress, and ferroptosis. It can affect cell fate by engaging in the complex relationships between senescence, death, and cancer. The influence of oxidative stress on tumorigenesis and progression is a multi-stage interlaced process that includes two aspects of promotion and inhibition, with mitochondria as the core of regulation. A deeper and more comprehensive understanding of the effects of oxidative stress on tumorigenesis is conducive to exploring more tumor therapies.

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“…Prevents AV fibrocalcification, protects mitochondrial biogenesis, and performances via OPA1 [116] MMP9 inhibitor MMP-9i…”

Section: Novel Insights On the Therapeutic Strategies Of Cavsmentioning

confidence: 99%

The Complex Relationship between Hypoxia Signaling, Mitochondrial Dysfunction and Inflammation in Calcific Aortic Valve Disease: Insights from the Molecular Mechanisms to Therapeutic Approaches

Bouhamida

Morciano

Pedriali

et al. 2023

IJMS

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Calcific aortic valve stenosis (CAVS) is among the most common causes of cardiovascular mortality in an aging population worldwide. The pathomechanisms of CAVS are such a complex and multifactorial process that researchers are still making progress to understand its physiopathology as well as the complex players involved in CAVS pathogenesis. Currently, there is no successful and effective treatment to prevent or slow down the disease. Surgical and transcatheter valve replacement represents the only option available for treating CAVS. Insufficient oxygen availability (hypoxia) has a critical role in the pathogenesis of almost all CVDs. This process is orchestrated by the hallmark transcription factor, hypoxia-inducible factor 1 alpha subunit (HIF-1α), which plays a pivotal role in regulating various target hypoxic genes and metabolic adaptations. Recent studies have shown a great deal of interest in understanding the contribution of HIF-1α in the pathogenesis of CAVS. However, it is deeply intertwined with other major contributors, including sustained inflammation and mitochondrial impairments, which are attributed primarily to CAVS. The present review aims to cover the latest understanding of the complex interplay effect of hypoxia signaling pathways, mitochondrial dysfunction, and inflammation in CAVS. We propose further hypotheses and interconnections on the complexity of these impacts in a perspective of better understanding the pathophysiology. These interplays will be examined considering recent studies that shall help us better dissect the molecular mechanism to enable the design and development of potential future therapeutic approaches that can prevent or slow down CAVS processes.

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PML at mitochondria-associated membranes governs a trimeric complex with NLRP3 and P2X7R that modulates the tumor immune microenvironment

Cited by 21 publications

References 39 publications

Novel Aryl Sulfonamide Derivatives as NLRP3 Inflammasome Inhibitors for the Potential Treatment of Cancer

Novel Aryl Sulfonamide Derivatives as NLRP3 Inflammasome Inhibitors for the Potential Treatment of Cancer

The Role of Oxidative Stress in Tumorigenesis and Progression

The Complex Relationship between Hypoxia Signaling, Mitochondrial Dysfunction and Inflammation in Calcific Aortic Valve Disease: Insights from the Molecular Mechanisms to Therapeutic Approaches

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