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Low human and murine Mcl-1 expression leads to a pro-apoptotic plaque phenotype enriched in giant-cells.

ABSTRACT: The anti-apoptotic protein myeloid cell leukemia 1 (Mcl-1) plays an important role in survival and differentiation of leukocytes, more specifically of neutrophils. Here, we investigated the impact of myeloid Mcl-1 deletion in atherosclerosis. Western type diet fed LDL receptor-deficient mice were transplanted with either wild-type (WT) or LysMCre Mcl-1^fl/fl (Mcl-1^-/-) bone marrow. Mcl-1 myeloid deletion resulted in enhanced apoptosis and lipid accumulation in atherosclerotic plaques. In vitro, Mcl-1 deficient macrophages also showed increased lipid accumulation, resulting in increased sensitivity to lipid-induced cell death. However, plaque size, necrotic core and macrophage content were similar in Mcl-1^-/- compared to WT mice, most likely due to decreased circulating and plaque-residing neutrophils. Interestingly, Mcl-1^-/- peritoneal foam cells formed up to 45% more multinucleated giant cells (MGCs) in vitro compared to WT, which concurred with an increased MGC presence in atherosclerotic lesions of Mcl-1^-/- mice. Moreover, analysis of human unstable atherosclerotic lesions also revealed a significant inverse correlation between MGC lesion content and Mcl-1 gene expression, coinciding with the mouse data. Taken together, these findings suggest that myeloid Mcl-1 deletion leads to a more apoptotic, lipid and MGC-enriched phenotype. These potentially pro-atherogenic effects are however counteracted by neutropenia in circulation and plaque.

SUBMITTER: Fontaine MAC

PROVIDER: S-EPMC6787218 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Low human and murine Mcl-1 expression leads to a pro-apoptotic plaque phenotype enriched in giant-cells.

Fontaine Margaux A C MAC Westra Marijke M MM Bot Ilze I Jin Han H Franssen Aimée J P M AJPM Bot Martine M de Jager Saskia C A SCA Dzhagalov Ivan I He You-Wen YW van Vlijmen Bart J M BJM Gijbels Marion J J MJJ Reutelingsperger Chris P CP van Berkel Theo J C TJC Sluimer Judith C JC Temmerman Lieve L Biessen Erik A L EAL

Scientific reports 20191010 1

The anti-apoptotic protein myeloid cell leukemia 1 (Mcl-1) plays an important role in survival and differentiation of leukocytes, more specifically of neutrophils. Here, we investigated the impact of myeloid Mcl-1 deletion in atherosclerosis. Western type diet fed LDL receptor-deficient mice were transplanted with either wild-type (WT) or LysMCre Mcl-1<sup>fl/fl</sup> (Mcl-1<sup>-/-</sup>) bone marrow. Mcl-1 myeloid deletion resulted in enhanced apoptosis and lipid accumulation in atheroscleroti ...[more]

PMID: 31601924

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Project description:Mitochondria play a central role in non-alcoholic fatty liver disease (NAFLD) progression and in the control of cell death signalling during the progression to hepatocellular carcinoma (HCC). Associated with the metabolic syndrome, NAFLD is mostly driven by insulin-resistant white adipose tissue lipolysis that results in an increased hepatic fatty acid influx and the ectopic accumulation of fat in the liver. Upregulation of beta-oxidation as one compensatory mechanism leads to an increase in mitochondrial tricarboxylic acid cycle flux and ATP generation. The progression of NAFLD is associated with alterations in the mitochondrial molecular composition and respiratory capacity, which increases their vulnerability to different stressors, including calcium and pro-inflammatory molecules, which result in an increased generation of reactive oxygen species (ROS) that, altogether, may ultimately lead to mitochondrial dysfunction. This may activate further pro-inflammatory pathways involved in the progression from steatosis to steatohepatitis (NASH). Mushroom-enriched diets, or the administration of their isolated bioactive compounds, have been shown to display beneficial effects on insulin resistance, hepatic steatosis, oxidative stress, and inflammation by regulating nutrient uptake and lipid metabolism as well as modulating the antioxidant activity of the cell. In addition, the gut microbiota has also been described to be modulated by mushroom bioactive molecules, with implications in reducing liver inflammation during NAFLD progression. Dietary mushroom extracts have been reported to have anti-tumorigenic properties and to induce cell-death via the mitochondrial apoptosis pathway. This calls for particular attention to the potential therapeutic properties of these natural compounds which may push the development of novel pharmacological options to treat NASH and HCC. We here review the diverse effects of mushroom-enriched diets in liver disease, emphasizing those effects that are dependent on mitochondria.

Project description:BH3-mimetic drugs are an anti-cancer therapy that can induce apoptosis in malignant cells by directly binding and inhibiting pro-survival proteins of the BCL-2 family. The BH3-mimetic drug venetoclax, which targets BCL-2, has been approved for the treatment of chronic lymphocytic leukaemia and acute myeloid leukaemia by regulatory authorities worldwide. However, while most patients initially respond well, resistance and relapse while on this drug is an emerging and critical issue in the clinic. Though some studies have begun uncovering the factors involved in resistance to BCL-2-targeting BH3-mimetic drugs, little focus has been applied to pre-emptively tackle resistance for the next generation of BH3-mimetic drugs targeting MCL-1, which are now in clinical trials for diverse blood cancers. Therefore, using pre-clinical mouse and human models of aggressive lymphoma, we sought to predict factors likely to contribute to the development of resistance in patients receiving MCL-1-targeting BH3-mimetic drugs. First, we performed multiple whole genome CRISPR/Cas9 KO screens and identified that loss of the pro-apoptotic effector protein BAX, but not its close relative BAK, could confer resistance to MCL-1-targeting BH3-mimetic drugs in both short-term and long-term treatment regimens, even in lymphoma cells lacking the tumour suppressor TRP53. Furthermore, we found that mouse Eµ-Myc lymphoma cells selected for loss of BAX, as well as upregulation of the untargeted pro-survival BCL-2 family proteins BCL-XL and A1, when made naturally resistant to MCL-1 inhibitors by culturing them in increasing doses of drug over time, a situation mimicking the clinical application of these drugs. Finally, we identified therapeutic approaches which could overcome these two methods of resistance: the use of chemotherapeutic drugs or combined BH3-mimetic treatment, respectively. Collectively, these results uncover some key factors likely to cause resistance to MCL-1 inhibition in the clinic and suggest rational therapeutic strategies to overcome resistance that should be investigated further.

Project description:Background & aimsMcl-1, an antiapoptotic protein overexpressed in many tumours, including hepatocellular carcinoma (HCC), represents a promising target for cancer treatment. Although Mcl-1 non-apoptotic roles might critically influence the therapeutic potential of Mcl-1 inhibitors, these functions remain poorly understood. We aimed to investigate the effects of hepatic Mcl-1 deficiency (Mcl-1Δhep) on hepatocyte ploidy and cell cycle in murine liver in vivo and the possible implications on HCC.MethodsLivers of young Mcl-1Δhep and wild-type (WT) mice were analysed for ploidy profile, mitotic figures, in situ chromosome segregation, gene set enrichment analysis and were subjected to two-thirds partial hepatectomy to assess Mcl-1 deficiency effect on cell cycle progression in vivo. Mcl-1Δhep tumours in older mice were analysed for ploidy profile, chromosomal instability, and mutational signatures via whole exome sequencing.ResultsIn young mice, Mcl-1 deficiency leads to nuclear polyploidy and to high rates of mitotic errors with abnormal spindle figures and chromosome mis-segregation along with a prolonged spindle assembly checkpoint activation signature. Chromosomal instability and altered ploidy profile are observed in Mcl-1Δhep tumours of old mice as well as a characteristic mutational signature of currently unknown aetiology.ConclusionsOur study suggests novel non-apoptotic effects of Mcl-1 deficiency on nuclear ploidy, mitotic regulation, and chromosomal segregation in hepatocytes in vivo. In addition, the Mcl-1 deficiency characteristic mutational signature might reflect mitotic issues. These results are of importance to consider when developing anti-Mcl-1 therapies to treat cancer.Impact and implicationsAlthough Mcl-1 inhibitors represent promising hepatocellular carcinoma treatment, the still poorly understood non-apoptotic roles of Mcl-1 might compromise their successful clinical application. Our study shows that Mcl-1 deficiency leads to nuclear polyploidy, mitotic errors, and aberrant chromosomal segregation in hepatocytes in vivo, whereas hepatocellular tumours spontaneously induced by Mcl-1 deficiency exhibit chromosomal instability and a mutational signature potentially reflecting mitotic issues. These results have potential implications for the development of anti-Mcl-1 therapies to treat hepatocellular carcinoma, especially as hyperproliferative liver is a clinically relevant situation.

Dataset Information

Low human and murine Mcl-1 expression leads to a pro-apoptotic plaque phenotype enriched in giant-cells.

Publications

Low human and murine Mcl-1 expression leads to a pro-apoptotic plaque phenotype enriched in giant-cells.

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