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Hypoxia inducible factor down-regulation, cancer and cancer stem cells (CSCs): ongoing success stories.

ABSTRACT: In cancers, hypoxia inducible factor 1 (HIF-1) is an over-expressed transcription factor, which regulates a large set of genes involved in tumour vascularization, metastases, and cancer stem cells (CSCs) formation and self-renewal. This protein has been identified as a relevant target in oncology and several HIF-1 modulators are now marketed or in advanced clinical trials. The purpose of this review is to summarize the advances in the understanding of its regulation and its inhibition, from the medicinal chemist point of view. To this end, we selected in the recent literature relevant examples of "hit" compounds, including small-sized organic molecules, pseudopeptides and nano-drugs, exhibiting in vitro and/or in vivo both anti-HIF-1 and anti-tumour activities. Whenever possible, a particular emphasis has been dedicated to compounds that selectively target CSCs.

SUBMITTER: Martin AR

PROVIDER: S-EPMC6071925 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Hypoxia inducible factor down-regulation, cancer and cancer stem cells (CSCs): ongoing success stories.

Martin Anthony R AR Ronco Cyril C Ronco Cyril C Demange Luc L Benhida Rachid R

MedChemComm 20161019 1

In cancers, hypoxia inducible factor 1 (HIF-1) is an over-expressed transcription factor, which regulates a large set of genes involved in tumour vascularization, metastases, and cancer stem cells (CSCs) formation and self-renewal. This protein has been identified as a relevant target in oncology and several HIF-1 modulators are now marketed or in advanced clinical trials. The purpose of this review is to summarize the advances in the understanding of its regulation and its inhibition, from the ...[more]

PMID: 30108689

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Project description:Background and aimsTherapeutic strategies against HBV focus, among others, on the activation of the immune system to enable the infected host to eliminate HBV. Hypoxia-inducible factor 1 alpha (HIF1α) stabilization has been associated with impaired immune responses. HBV pathogenesis triggers chronic hepatitis-related scaring, leading inter alia to modulation of liver oxygenation and transient immune activation, both factors playing a role in HIF1α stabilization.Approach and resultsWe addressed whether HIF1α interferes with immune-mediated induction of the cytidine deaminase, apolipoprotein B mRNA editing enzyme catalytic subunit 3B (APOBEC3B; A3B), and subsequent covalently closed circular DNA (cccDNA) decay. Liver biopsies of chronic HBV (CHB) patients were analyzed by immunohistochemistry and in situ hybridization. The effect of HIF1α induction/stabilization on differentiated HepaRG or mice ± HBV ± LTβR-agonist (BS1) was assessed in vitro and in vivo. Induction of A3B and subsequent effects were analyzed by RT-qPCR, immunoblotting, chromatin immunoprecipitation, immunocytochemistry, and mass spectrometry. Analyzing CHB highlighted that areas with high HIF1α levels and low A3B expression correlated with high HBcAg, potentially representing a reservoir for HBV survival in immune-active patients. In vitro, HIF1α stabilization strongly impaired A3B expression and anti-HBV effect. Interestingly, HIF1α knockdown was sufficient to rescue the inhibition of A3B up-regulation and -mediated antiviral effects, whereas HIF2α knockdown had no effect. HIF1α stabilization decreased the level of v-rel reticuloendotheliosis viral oncogene homolog B protein, but not its mRNA, which was confirmed in vivo. Noteworthy, this function of HIF1α was independent of its partner, aryl hydrocarbon receptor nuclear translocator.ConclusionsIn conclusion, inhibiting HIF1α expression or stabilization represents an anti-HBV strategy in the context of immune-mediated A3B induction. High HIF1α, mediated by hypoxia or inflammation, offers a reservoir for HBV survival in vivo and should be considered as a restricting factor in the development of immune therapies.

Dataset Information

Hypoxia inducible factor down-regulation, cancer and cancer stem cells (CSCs): ongoing success stories.

Publications

Hypoxia inducible factor down-regulation, cancer and cancer stem cells (CSCs): ongoing success stories.

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