Calcitriol Suppresses HIF-1 and HIF-2 Transcriptional Activity by Reducing HIF-1/2α Protein Levels via a VDR-Independent Mechanism

Gkotinakou, Ioanna-Maria; Kechagia, Eleni; Pazaitou‐Panayiotou, Kalliopi; Mylonis, Ilias; Liakos, Panagiotis; Tsakalof, Andreas

doi:10.3390/cells9112440

Cited by 17 publications

(11 citation statements)

References 75 publications

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“…Transcription can be inhibited by different kinds of compounds, such as aminoflavone [ 124 ], GL331 [ 125 ], and anthracyclines [ 126 ]. Other compounds belonging to cardiac glycosides [ 127 ], steroids [ 128 ], topoisomerase inhibitors [ 129 ], and microtubule binding agents [ 130 ] show the inhibitory effect of translation rate of HIF mRNA by different mechanisms. However, these compounds lack specificity on isoforms.…”

Section: Targeting Hif-1 In Cancer Therapymentioning

confidence: 99%

Cancer Cell Metabolism in Hypoxia: Role of HIF-1 as Key Regulator and Therapeutic Target

Infantino

Santarsiero

Convertini

et al. 2021

IJMS

232

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In order to meet the high energy demand, a metabolic reprogramming occurs in cancer cells. Its role is crucial in promoting tumor survival. Among the substrates in demand, oxygen is fundamental for bioenergetics. Nevertheless, tumor microenvironment is frequently characterized by low-oxygen conditions. Hypoxia-inducible factor 1 (HIF-1) is a pivotal modulator of the metabolic reprogramming which takes place in hypoxic cancer cells. In the hub of cellular bioenergetics, mitochondria are key players in regulating cellular energy. Therefore, a close crosstalk between mitochondria and HIF-1 underlies the metabolic and functional changes of cancer cells. Noteworthy, HIF-1 represents a promising target for novel cancer therapeutics. In this review, we summarize the molecular mechanisms underlying the interplay between HIF-1 and energetic metabolism, with a focus on mitochondria, of hypoxic cancer cells.

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Section: Targeting Hif-1 In Cancer Therapymentioning

confidence: 99%

Cancer Cell Metabolism in Hypoxia: Role of HIF-1 as Key Regulator and Therapeutic Target

Infantino

Santarsiero

Convertini

et al. 2021

IJMS

232

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“…EPAS1 is a homolog of hypoxia-inducible factor 1α. It plays essential roles in cell survival and invasion through E-cadherin, Vimentin, Ki-67, CD31 14 , and VEGFA 15 16 . It has been associated with several human cancers 17 .…”

Section: Introductionmentioning

confidence: 99%

MiR-182-5p promotes the Metastasis and Epithelial-mesenchymal Transition in Non-small Cell Lung Cancer by Targeting EPAS1

Yang¹,

Yin²,

Bi³

et al. 2021

J. Cancer

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Background: Dysregulation of microRNAs (miRNAs) is associated with the pathogenesis of non-small cell lung cancer (NSCLC). However, the mechanisms through which miR-182-5p regulate NSCLC progression have not been established. This study aimed at evaluating the expression levels of miR-182-5p in human NSCLC and its function in lung cancer cells. Endothelial PAS Domain-containing protein 1 (EPAS1; also referred to as hypoxia-inducing factor 2A, HIF-2α) is a transcription factor that is responsible for induction of genes related to cell survival under hypoxia conditions. Hypoxia, an inherent feature of solid tumors, is associated with aggressive phenotypes, as well as resistance to radiotherapy and chemotherapy, which predict metastasis and poor prognosis. Methods: The Cancer Genome Atlas (TCGA) dataset was used to investigate the association between miR-182-5p expression and clinicopathological characteristics as well as prognosis of NSCLC patients. Target genes of miR-182-5p were identified using the PITA, miRmap, microT, miRanda, PicTar, and TargetScan prediction tools. Transwell assays were performed to determine the potential functions of miR-182-5p in lung cancer cells. Luciferase reporter assays were performed to analyze regulation of the putative target of miR-182-5p while western blot assays were used to validate the luciferase results. Results: miR-182-5p was found to be upregulated in NSCLC tissues and acted as an independent prognostic factor for tumor recurrence in NSCLC patients. Functionally, overexpression of miR-182-5p promoted lung cancer cell migration and invasion. Genome-wide gene expression analysis and luciferase report assays revealed that EPAS1 is a direct target of miR-182-5p. EPAS1 was negatively correlated with miR-182-5p expression in NSCLC tissues. Univariate and multivariate survival analyses identified EPAS1 as an independent prognostic factor for overall survival (OS) in NSCLC. Conclusions: These findings imply that miR-182-5p promotes NSCLC progression by targeting EPAS1 and is, therefore, a potential indicator of tumor recurrence in NSCLC patients.

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“…Treating hepatoma cells with calcitriol resulted in HIF1A and EPAS1 mRNAs localization in ribosomal fractions that are associated with low translation rates. Furthermore, calcitriol treatment resulted in decreased phosphorylation levels of AKT and downstream translation initiation factors ( Figure 3 ) [ 116 ].…”

Section: Vitamin D Crosstalk With Hif Signalingmentioning

confidence: 99%

Vitamin D and Hypoxia: Points of Interplay in Cancer

Gkotinakou

Mylonis

Tsakalof

2022

Cancers

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Vitamin D is a hormone that, through its action, elicits a broad spectrum of physiological responses ranging from classic to nonclassical actions such as bone morphogenesis and immune function. In parallel, many studies describe the antiproliferative, proapoptotic, antiangiogenic effects of calcitriol (the active hormonal form) that contribute to its anticancer activity. Additionally, epidemiological data signify the inverse correlation between vitamin D levels and cancer risk. On the contrary, tumors possess several adaptive mechanisms that enable them to evade the anticancer effects of calcitriol. Such maladaptive processes are often a characteristic of the cancer microenvironment, which in solid tumors is frequently hypoxic and elicits the overexpression of Hypoxia-Inducible Factors (HIFs). HIF-mediated signaling not only contributes to cancer cell survival and proliferation but also confers resistance to anticancer agents. Taking into consideration that calcitriol intertwines with signaling events elicited by the hypoxic status cells, this review examines their interplay in cellular signaling to give the opportunity to better understand their relationship in cancer development and their prospect for the treatment of cancer.

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Calcitriol Suppresses HIF-1 and HIF-2 Transcriptional Activity by Reducing HIF-1/2α Protein Levels via a VDR-Independent Mechanism

Cited by 17 publications

References 75 publications

Cancer Cell Metabolism in Hypoxia: Role of HIF-1 as Key Regulator and Therapeutic Target

Cancer Cell Metabolism in Hypoxia: Role of HIF-1 as Key Regulator and Therapeutic Target

MiR-182-5p promotes the Metastasis and Epithelial-mesenchymal Transition in Non-small Cell Lung Cancer by Targeting EPAS1

Vitamin D and Hypoxia: Points of Interplay in Cancer

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