Tumor suppressor p53 and estrogen receptors in nuclear–mitochondrial communication

Wickramasekera, Nadi; Das, Gokul M.

doi:10.1016/j.mito.2013.10.002

Cited by 21 publications

(14 citation statements)

References 151 publications

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“…When the metabolic activity is compromised, specific pathways have to be activated in order to optimize it 18 , 25 – 31 . Therefore, we investigated intracellular signalling pathways underlying the metabolic adaptation of the cells to the mitochondrial defects, such as the mitogenesis-related PGC1α axis and CREB (cAMP responsive element binding protein) pathway 32 – 37 .…”

Section: Resultsmentioning

confidence: 99%

Energetic mitochondrial failing in vitiligo and possible rescue by cardiolipin

Dell’Anna

Ottaviani

Kovacs

et al. 2017

Sci Rep

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Vitiligo is characterized by death or functional defects of epidermal melanocytes through still controversial pathogenic process. Previously, we showed that mitochondria-driven pre-senescent phenotype diminishes the capability of vitiligo melanocytes to cope with stressful stimuli. In the current study, we investigated markers of mitochondrial energy metabolism including the PGC1a axis, and then we determined the index of mitochondrial impairment using a cytomic approach. We found in cultured epidermal vitiligo melanocytes, compared to healthy ones, low ATP, increased proton leakage, and altered expression of several glycolytic enzymes (hexokinase II, pyruvic dehydrogenase kinase 1 and pyruvic kinase M2), We suggest that the low ATP production may be sufficient in steady-state conditions but it is unable to cover further needs. We also found in vitiligo melanocyrtes hyper-activation of the PGC1α axis, finalized to counteract the energy defect. Cytomic analysis, supported by MitoTracker Red pattern and ex-vivo immunohistochemistry, suggested an increased mitochondrial mass, possibly useful to ensure the essential ATP level. Finally, pharmacological cardiolipin stabilization reverted the energetic impairment, confirming the initial mitochondrial role. In conclusion, we report new insight in the pathogenetic mechanism of viitligo and indicate that the mitochondrial failure rescue by cardiolipin manipulation may be a new intriguing target in treatment development.

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Section: Resultsmentioning

confidence: 99%

Energetic mitochondrial failing in vitiligo and possible rescue by cardiolipin

Dell’Anna

Ottaviani

Kovacs

et al. 2017

Sci Rep

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“…[33,54,55] Combination of either 3BP or 2DG with the CYP2E1 inhibitor CMZ reduced dramatically the oxygen radicals' levels in the MCF-7 but not in the MDA-MB-231 cells [ Figure 2] implying that the dissimilar genetic background in the two cell lines (wild type ER and p53 in MCF-7 and defective ER and mutated p53 in MDA-MB-231 cells) determines the differential response of these cells to the glycolytic and CYP2E1 inhibitors. [56] The observation that CMZ decreased ROS generation stimulated by 3BP and 2DG treatment in MCF-7 cells prompted our interest to explore the possibility that CYP2E1 is involved in the process of energy metabolism in breast cancer cells. The potential link between CYP2E1 and energy metabolism was investigated in the MCF-7 and MDA-MB-231 cells by estimating the ATP production after treating these cells with the CYP2E1 inhibitor CMZ.…”

Section: Discussionmentioning

confidence: 99%

Oxidative stress and breast cancer biomarkers: the case of the cytochrome P450 2E1

Singh

Rajendran

Kuroda

et al. 2016

JCMT

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Aim:The aim of the study is to investigate the impact of the cytochrome P450 2E1, which is the most efficient CYP450 family member in generating reactive oxygen species (ROS), on cellular energy metabolism of breast cancer cells and therefore the effects of CYP2E1 on breast carcinogenesis. Methods: The estrogen receptor positive MCF-7 and the triple negative MDA-MB-231 breast cancer cells were used as experimental system to estimate ROS generation in these cells overexpressing CYP2E1 and treated with the glycolytic inhibitors 3-bromopyruvate or 2-deoxyglucose in the presence or absence of the CYP2E1 inhibitor chlormethiazole. Adenosine triphosphate (ATP) assay was used to measure ATP production and lactate assay to quantify the efflux of lactic acid in breast cancer cells treated with the CYP2E1 inhibitor chlormethiazole, the mitochondrial membrane potential and cell viability assays were employed to assess the pathway of cellular energy production and cellular death respectively after treatment of MCF-7 and MDA-MB-231 with the CYP2E1 activator acetaminophen or the CYP2E1 inhibitor chlormethiazole. Results:The results indicated increased ROS generation in breast cancer cells overexpressing CYP2E1. ROS generation was differentially regulated in breast cancer cells upon treatment with the CYP2E1 inhibitor chlormethiazole. Chlormethiazole treated MCF-7 cells exhibited reduced lactate efflux implying that CYP2E1 directly or indirectly regulates the glycolytic rate in these cells. Furthermore the mitochondrial membrane potential of both MCF-7 and MDA-MB-231 cells was differentially affected by the CYP2E1 activator acetaminophen versus the CYP2E1 inhibitor chlormethiazole providing additional support for the involvement of CYP2E1 in energy metabolic pathways in breast cancer. Conclusion: Results presented in this study provide evidence to suggest that CYP2E1 regulates cellular energy metabolism of breast cancer cells in a manner dependent on cell type and potentially on the clinical staging of the disease therefore CYP2E1 is a possible breast cancer biomarker.

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“…mtDNA variants have the potential to induce molecular signals through the mitochondrial-nuclear crosstalk mechanism, thereby promoting nuclear compensation in response to mitochondrial malfunction [67]. Interestingly, some typical nuclear transcription factors, such as the tumor-suppressor p53 and estrogen receptor (ER), are localized within mitochondria, where they exert various transcriptionindependent functions [83]. By using transmitochondrial cybrid systems ("cybrids"), Kaipparettu et al [69] elegantly demonstrated that mitochondria derived from the non-transformed breast epithelial cell line MCF10A reverse the tumorigenic properties of osteosarcoma metastatic cells (e.g.…”

Section: Mitochondrial-nuclear Crosstalkmentioning

confidence: 99%

Mitochondrial DNA Variations in Tumors: Drivers or Passengers?

Errichiello¹,

Venesio²

2018

Mitochondrial DNA - New Insights

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Mitochondrial DNA alterations, including point mutations, deletions, inversions and copy number variations, have been widely reported in many age-related degenerative diseases and tumors. However, numerous studies investigating their pathogenic role in cancer have provided inconsistent evidence. Furthermore, biological impacts of mitochondrial DNA variants vary tremendously, depending on the proportion of mutant DNA molecules carried by the neoplastic cells (the so-called heteroplasmy). The recent discovery of inter-genomic crosstalk between nucleus and mitochondria has reinforced the role of mitochondrial DNA variants in perturbing this essential signaling pathway and thus indirectly targeting nuclear genes involved in tumorigenic and invasive phenotype. Therefore, mitochondrial dysfunction is currently considered a crucial hallmark of carcinogenesis as well as a promising target for anticancer therapy. This chapter describes the role of different types of mitochondrial DNA alterations by mainly considering the paradigmatic model of colorectal carcinogenesis and, in particular, it revisits the issue of whether mitochondrial mutations are causative cancer drivers or simply genuine passenger events. The advent of high-throughput next-generation sequencing techniques, as well as the development of genetic and pharmaceutical interventions for the treatment of mitochondrial dysfunction in cancer, are also discussed.

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Tumor suppressor p53 and estrogen receptors in nuclear–mitochondrial communication

Cited by 21 publications

References 151 publications

Energetic mitochondrial failing in vitiligo and possible rescue by cardiolipin

Energetic mitochondrial failing in vitiligo and possible rescue by cardiolipin

Oxidative stress and breast cancer biomarkers: the case of the cytochrome P450 2E1

Mitochondrial DNA Variations in Tumors: Drivers or Passengers?

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