LXR Signaling Regulates Macrophage Survival and Inflammation in Response to Ionizing Radiation

Tabraue, Carlos; Lara, Pedro C.; Mirecki-Garrido, Mercedes de; Rosa, Juan Vladimir de la; Blanco, F. López; Fernández-Pérez, Leandro; Castrillo, Antonio

doi:10.1016/j.ijrobp.2019.03.028

Cited by 21 publications

(13 citation statements)

References 41 publications

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“…Therefore, Derangere et al believe that the LXR ligand and LXR receptor combination can open the pannexin-1 channel and release ATP, and high extracellular ATP participates in the activation of P2X7 receptor and caspase-1, inducing the formation of NLRP3 inflammasomes and thereby promoting the nonclassical pyroptosis of CAC cells 124 . Furthermore, the genetic and pharmacological inactivation of LXR in murine bone marrow-derived macrophages enhanced the inhibitory effects of radiation therapy on tumor growth through the induction of pyroptosis and activation of the inflammatory cascade 125 (Fig. 3).…”

Section: Manipulating Pyroptosis For Therapeutic Benefitmentioning

confidence: 99%

The role of pyroptosis in cancer: pro-cancer or pro-“host”?

et al. 2019

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Programmed cell death (PCD) refers to the way in which cells die depending on specific genes encoding signals or activities. Apoptosis, autophagy, and pyroptosis are all mechanisms of PCD. Among these mechanisms, pyroptosis is mediated by the gasdermin family, accompanied by inflammatory and immune responses. The relationship between pyroptosis and cancer is complex, and the effects of pyroptosis on cancer vary in different tissues and genetic backgrounds. On one hand, pyroptosis can inhibit the occurrence and development of tumors; on the other hand, as a type of proinflammatory death, pyroptosis can form a suitable microenvironment for tumor cell growth and thus promote tumor growth. In addition, the induction of tumor pyroptosis is also considered a potential cancer treatment strategy. Studies have shown that DFNA5 (nonsyndromic hearing impairment protein 5)/GSDME (Gasdermin-E) mRNA methylation results in lower expression levels of DFNA5/GSDME in most tumor cells than in normal cells, making it difficult to activate the pyroptosis in most tumor cells. During the treatment of malignant tumors, appropriate chemotherapeutic drugs can be selected according to the expression levels of DFNA5/GSDME, which can be upregulated in tumor cells, thereby increasing the sensitivity to chemotherapeutic drugs and reducing drug resistance. Therefore, induced pyroptosis may play a predominant role in the treatment of cancer. Here, we review the latest research on the anti-and protumor effects of pyroptosis and its potential applications in cancer treatment. Facts Open questions 1. Does pyroptosis play differential roles in normal and tumor tissues? 2. What are the key signals that initiate pyroptosis? 3. What are the key signaling pathways impacted by pyroptosis in tumors? 4. How can pyroptosis be manipulated to drive tumor fate?

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Section: Manipulating Pyroptosis For Therapeutic Benefitmentioning

confidence: 99%

The role of pyroptosis in cancer: pro-cancer or pro-“host”?

et al. 2019

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“…Interestingly, many studies have shown that STAT activity is essential to localize, maintain, and renew Hematopoietic Stem/Progenitors cells (HSPC) into tumoral niche and that STAT hyperactivation is associated with uncontrolled proliferation of HSPC (151)(152)(153)(154)(155). Thereby, dual strategies targeting both tumor cell proliferation and tumor niche and/or regulation of TIM represent a promising therapeutic strategy (156,157). Interestingly, the effects of MVA biosynthetic pathway inhibitors (i.e., statins, bisphosphonates) on TAMs suggest that TIM can be regulated by MVA biosynthetic pathway (158)(159)(160).…”

Section: Signal Transducers and Activators Of Transcription (Stat)mentioning

confidence: 99%

The Mevalonate Pathway, a Metabolic Target in Cancer Therapy

et al. 2021

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A hallmark of cancer cells includes a metabolic reprograming that provides energy, the essential building blocks, and signaling required to maintain survival, rapid growth, metastasis, and drug resistance of many cancers. The influence of tumor microenviroment on cancer cells also results an essential driving force for cancer progression and drug resistance. Lipid-related enzymes, lipid-derived metabolites and/or signaling pathways linked to critical regulators of lipid metabolism can influence gene expression and chromatin remodeling, cellular differentiation, stress response pathways, or tumor microenviroment, and, collectively, drive tumor development. Reprograming of lipid metabolism includes a deregulated activity of mevalonate (MVA)/cholesterol biosynthetic pathway in specific cancer cells which, in comparison with normal cell counterparts, are dependent of the continuous availability of MVA/cholesterol-derived metabolites (i.e., sterols and non-sterol intermediates) for tumor development. Accordingly, there are increasing amount of data, from preclinical and epidemiological studies, that support an inverse association between the use of statins, potent inhibitors of MVA biosynthetic pathway, and mortality rate in specific cancers (e.g., colon, prostate, liver, breast, hematological malignances). In contrast, despite the tolerance and therapeutic efficacy shown by statins in cardiovascular disease, cancer treatment demands the use of relatively high doses of single statins for a prolonged period, thereby limiting this therapeutic strategy due to adverse effects. Clinically relevant, synergistic effects of tolerable doses of statins with conventional chemotherapy might enhance efficacy with lower doses of each drug and, probably, reduce adverse effects and resistance. In spite of that, clinical trials to identify combinatory therapies that improve therapeutic window are still a challenge. In the present review, we revisit molecular evidences showing that deregulated activity of MVA biosynthetic pathway has an essential role in oncogenesis and drug resistance, and the potential use of MVA pathway inhibitors to improve therapeutic window in cancer.

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“…Following irradiation in LXR-deficient BMDMs, significantly increased p53 expression, caspase-1 activity and subsequent pyroptosis, as well as pro-inflammatory cytokine production was detected. They concluded that ionizing radiation of LXR-deficient or LXR antagonist-pretreated macrophages promoted macrophage polarization toward a pro-inflammatory (M1) type, however, irradiation markedly reduced their viability as a result of the enhanced pyroptosis (180).…”

Section: Pregnane X Receptor (Pxr)mentioning

confidence: 99%

Nuclear Receptors as Multiple Regulators of NLRP3 Inflammasome Function

Alatshan

Benkő

2021

Front. Immunol.

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Nuclear receptors are important bridges between lipid signaling molecules and transcription responses. Beside their role in several developmental and physiological processes, many of these receptors have been shown to regulate and determine the fate of immune cells, and the outcome of immune responses under physiological and pathological conditions. While NLRP3 inflammasome is assumed as key regulator for innate and adaptive immune responses, and has been associated with various pathological events, the precise impact of the nuclear receptors on the function of inflammasome is hardly investigated. A wide variety of factors and conditions have been identified as modulators of NLRP3 inflammasome activation, and at the same time, many of the nuclear receptors are known to regulate, and interact with these factors, including cellular metabolism and various signaling pathways. Nuclear receptors are in the focus of many researches, as these receptors are easy to manipulate by lipid soluble molecules. Importantly, nuclear receptors mediate regulatory mechanisms at multiple levels: not only at transcription level, but also in the cytosol via non-genomic effects. Their importance is also reflected by the numerous approved drugs that have been developed in the past decade to specifically target nuclear receptors subtypes. Researches aiming to delineate mechanisms that regulate NLRP3 inflammasome activation draw a wide range of attention due to their unquestionable importance in infectious and sterile inflammatory conditions. In this review, we provide an overview of current reports and knowledge about NLRP3 inflammasome regulation from the perspective of nuclear receptors, in order to bring new insight to the potentially therapeutic aspect in targeting NLRP3 inflammasome and NLRP3 inflammasome-associated diseases.

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LXR Signaling Regulates Macrophage Survival and Inflammation in Response to Ionizing Radiation

Cited by 21 publications

References 41 publications

The role of pyroptosis in cancer: pro-cancer or pro-“host”?

The role of pyroptosis in cancer: pro-cancer or pro-“host”?

The Mevalonate Pathway, a Metabolic Target in Cancer Therapy

Nuclear Receptors as Multiple Regulators of NLRP3 Inflammasome Function

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