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Transcriptome analysis of SH-SY5Y neuroblastoma cells treated with copper and copper chelators (Dextran-Catechin - DC, and Tetraethylenepentamine pentahydrochloride - TEPA) in the presence or absence of interferon gamma

ABSTRACT: Therapeutic checkpoint antibodies blocking PD1/PD-L1 signaling have radically improved clinical outcomes in cancer. However, the regulation of PD-L1 expression on tumor cells is still poorly understood. Here we show that intra-tumoral copper levels influence PD-L1 expression in cancer cells. Copper supplementation enhanced PD-L1 expression at mRNA and protein levels in cancer cells and RNAseq revealed that copper regulates key signaling pathways mediating PD-L1-driven cancer immune evasion. Conversely, copper chelators inhibited phosphorylation of STAT3 and EGFR and promoted ubiquitin-mediated degradation of PD-L1. Overall, this study reveals an important role for copper in regulating PD-L1 and suggests that anti-cancer immunotherapy might be enhanced by pharmacologically reducing intra-tumor copper levels.

ORGANISM(S): Homo sapiens

PROVIDER: GSE155031 | GEO | 2020/07/28

REPOSITORIES: GEO

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Transcriptome analysis of SH-SY5Y neuroblastoma cells treated with copper and copper chelators (Dextran-Catechin - DC, and Tetraethylenepentamine pentahydrochloride - TEPA) in the presence or absence of interferon gamma

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Project description:Iron and copper are important environmental nutrients for plant growth. However, the molecular mechanisms of both iron and copper signaling that integrate the two pathways remain poorly understood. The Arabidopsis thaliana high affinity copper transporter COPT5, is a tonoplast localized permease involved in copper remobilization. Here, a global expression microarray analysis of the copt5 mutant points out the induction of iron deficiency responses, including NATURAL RESISTANCE-ASSOCIATED MACROPHAGE PROTEIN 4 (NRAMP4), a tonoplast-localized iron transporter. The copper requirement in iron perception and uptake from the media becomes more evident in the double nramp3nramp4 mutant, unable to remobilize iron from vacuoles, that is highly sensitive to copper deficiency. Furthermore, COPT5 expression is altered under iron deficiency and the copt5 mutant is sensitive to iron deficiency and is unable to perceive iron in the media under copper deficiency. Noteworthy, iron deficiency post-transcriptionally restraints the copper-dependent superoxide dismutase protein levels and the subsequent activity. As a consequence of its increased iron deficiency responses, the copt5 mutant present lower levels of both copper- and iron-dependent superoxide dismutase activities. Moreover, the copt5 mutant mobilizes faster its iron storage pools and presents higher levels of iron in cotyledons and seeds. These results underline the importance of internal metal pools in the understanding of copper and iron deficiency responses and their crosstalk that are critical for governing proper plant development in response to combined metal scarcities in soils.

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Iron Chelators Treatment on MCF-7 Human Breast Cancer Cell

Project description:Iron-deficiency affects 500 million people, yet the molecular role of iron in gene expression remains poorly characterized. Moreover, the alterations in global gene expression after iron chelation remains unclear and are important to assess for understanding the molecular pathology of iron-deficiency and the biological effects of iron chelators. We assessed the effect on whole genome gene expression of two iron chelators (desferrioxamine and 2-hydroxy-1-napthylaldehyde isonicotinoyl hydrazone) that have markedly different permeability properties. Sixteen genes were significantly regulated by both chelators, while a further 50 genes were regulated by either ligand. Most of the genes identified in this study have not been previously described to be iron-regulated and are important for understanding the molecular and cellular effects of iron-deficiency. The MCF-7 cells were incubated with either control medium or this medium containing DFO (250 ÂµM) or 311 (25 ÂµM) for 24 h at 37oC. These concentrations were used since our previous studies demonstrated that under these conditions these chelators lead to up-regulation of iron-responsive genes such as the TfR1 after this incubation time.8 Moreover, the higher concentration of DFO was implemented due to its limited ability to permeate cell membranes. Total RNA was isolated from cells in 1 mL of TRIzolÂ® reagent (Invitrogen). Samples were then prepared and hybridized to the Human Genome U133 Plus 2.0 430 2.0. The human GeneChipÂ® U133 Plus 2.0 consists of greater than 47,000 transcripts and variants from over 38,500 well characterized human genes. On completion of hybridization and washing, microarray chips were scanned with the Affymetrix GeneChipÂ® Scanner 3000 (Affymetrix).

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