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Mutant p53 mediates sensitivity to cancer treatment agents in oesophageal adenocarcinoma associated with microRNA and SLC7A11 expression

ABSTRACT: 1) Background: TP53 gene mutations occur in 70% of oesophageal adenocarcinomas (OACs). Given the central role of p53 in controlling cellular response to therapy we investigated the role of mutant (mut-) p53 and SLC7A11 in a CRISPR-mediated JH-EsoAd1 TP53 knockout model. (2) Methods: Response to 2 Gy irradiation, cisplatin, 5-FU, 4-hydroxytamoxifen and endoxifen was assessed, followed by a TaqMan OpenArray qPCR screening for differences in miRNA expression. (3) Results: Knockout of mut-p53 resulted in increased chemo- and radioresistance (2 Gy survival fraction: 38% vs. 56%, p<0.0001) and in altered miRNA expression levels. Target mRNA pathways analyses indicated several potential mechanisms of treatment resistance. SLC7A11 knockdown restored radiosensitivity (2 Gy SF: 46% vs. 73%; p=0.0239), possibly via enhanced sensitivity to oxidative stress. Pathway analysis of the predicted mRNA targets of differentially expressed miRNAs indicated potential involvement in several pathways associated with apoptosis, ribosomes as well as in p53 signalling pathways. (4) Discussion: These results provide a better understanding of the important role of SLC7A11 in cancer metabolism and redox balance and the influence of p53 on these processes. Inhibition of the SLC7A11-gluthatione axis may represent a promising approach to overcome resistance associated with mut-p53.

ORGANISM(S): Homo sapiens

PROVIDER: GSE171965 | GEO | 2021/05/31

REPOSITORIES: GEO

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Hierarchy of mono- and bi-allelic TP53 alterations in Multiple Myeloma cell fitness

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A p53 score derived from TP53 CRISPR/Cas9 HMCLs predicts survival and reveals major role of BAX in BH3 mimetics response [1]

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2014-01-08 | E-GEOD-53893 | biostudies-arrayexpress

Mutant p53 mediates sensitivity to cancer treatment agents in oesophageal adenocarcinoma associated with microRNA and SLC7A11 expression

Project description:Mutant p53 mediates sensitivity to cancer treatment agents in oesophageal adenocarcinoma associated with microRNA and SLC7A11 expression

| PRJNA721462 | ENA

RRAD, IL4I1, CDKN1A, and SERPINE1 genes are potentially co-regulated by NF-κB and p53 transcription factors in cells exposed to high doses of ionizing radiation [RNA-Seq]

Project description:Cellular response to ionizing radiation involves activation of the p53-dependent pathways and activation of the atypical NF-?B pathway. Mechanisms of the crosstalk between these two transcriptional networks include (co)regulation of common gene targets. Novel genes potentially (co)regulated by p53 and NF-?B were found using high-throughput genomics screening in human osteosarcoma U2-OS cells irradiated with a high dose (4 and 10 Gy). Radiation-induced expression in cells with silenced TP53 or RELA (coding the p65 NF-?B subunit) genes was analyzed by RNA-Seq while radiation-induced binding of p53 and RelA (p65) in putative regulatory regions was analyzed by ChIP-Seq, then selected candidates were validated by qPCR. A subset of radiation-modulated genes whose expression was affected by silencing of both TP53 and RELA, and a subset of radiation-upregulated genes where radiation stimulated binding of both p53 and RelA were identified. Competition for the same transcriptional coactivators of p53 and NF-?B was the most probable mechanism of a frequent antagonistic effect of the TP53 and RELA silencing. However, this mode of regulation was noted for 3 genes where radiation-induced binding of both p53 and RelA was observed, namely IL4I1, SERPINE1, and CDKN1A. This suggested a possibility of a direct antagonistic (co)regulation by both factors: activation by NF-?B and inhibition by p53 of IL4I1, and activation by p53 and inhibition by NF-?B of CDKN1A and SERPINE1. On the other hand, radiation-induced binding of both p53 and RelA was observed in a putative regulatory region of RRAD gene whose expression was downregulated both by TP53 and RELA silencing, which suggested a possibility of direct (co)activation by both factors.

2018-02-17 | GSE110762 | GEO

RRAD, IL4I1, CDKN1A, and SERPINE1 genes are potentially co-regulated by NF-κB and p53 transcription factors in cells exposed to high doses of ionizing radiation [ChIP-Seq]

Project description:Cellular response to ionizing radiation involves activation of the p53-dependent pathways and activation of the atypical NF-κB pathway. Mechanisms of the crosstalk between these two transcriptional networks include (co)regulation of common gene targets. Novel genes potentially (co)regulated by p53 and NF-κB were found using high-throughput genomics screening in human osteosarcoma U2-OS cells irradiated with a high dose (4 and 10 Gy). Radiation-induced expression in cells with silenced TP53 or RELA (coding the p65 NF-κB subunit) genes was analyzed by RNA-Seq while radiation-induced binding of p53 and RelA (p65) in putative regulatory regions was analyzed by ChIP-Seq, then selected candidates were validated by qPCR. A subset of radiation-modulated genes whose expression was affected by silencing of both TP53 and RELA, and a subset of radiation-upregulated genes where radiation stimulated binding of both p53 and RelA were identified. Competition for the same transcriptional coactivators of p53 and NF-κB was the most probable mechanism of a frequent antagonistic effect of the TP53 and RELA silencing. However, this mode of regulation was noted for 3 genes where radiation-induced binding of both p53 and RelA was observed, namely IL4I1, SERPINE1, and CDKN1A. This suggested a possibility of a direct antagonistic (co)regulation by both factors: activation by NF-κB and inhibition by p53 of IL4I1, and activation by p53 and inhibition by NF-κB of CDKN1A and SERPINE1. On the other hand, radiation-induced binding of both p53 and RelA was observed in a putative regulatory region of RRAD gene whose expression was downregulated both by TP53 and RELA silencing, which suggested a possibility of direct (co)activation by both factors.

2018-02-19 | GSE110800 | GEO

Endoxifen Downregulates AKT Phosphorylation Through Protein Kinase C Beta 1 in ER+/HER2- Breast Cancer

Project description:In phase I/II clinical trials, Z-endoxifen demonstrated substantial oral bioavailability and promising antitumor activity in endocrine-refractory estrogen-receptor positive breast cancer (ER+ BC) and other solid tumors, with plasma concentrations reportedly as high as 5 ï�M. Therefore, we explored the potential mechanisms of Z-endoxifen antitumor activity that extends beyond ERÎ± inhibition. In estrogen unstimulated aromatase-expressing ER+/human epidermal growth factor 2 receptor negative (HER2-) MCF7AC1 BC cells, Z-endoxifen at 5 ï�M, but not ERï�¡-targeting 0.01 and 0.1 ï�M concentrations inhibited growth and induced apoptosis, suggesting an ERÎ±-independent effect. Utilizing an unbiased mass spectrometry approach, we explored Z-endoxifen effects on other signaling pathways. Z-endoxifen at 5 ÂµM profoundly altered the phosphoproteome with minimal impact on total proteome. Computational analysis revealed Protein kinase C beta (PKCï�¢) and AKT1 as the prevalent upstream kinases for Z-endoxifen-downregulated protein phosphorylations. Notably, in ER+/HER2- BC models, Z-endoxifen at 5 ï�M attenuated AKTSer473 and AKT substrates in vitro in the presence of insulin and PKC agonist PMA and in vivo. Further, Z-endoxifen inhibited PKCï�¢1 kinase activity compared to other PKC isoforms in vitro and bound to PKCÎ²1. While PMA stimulated PKCï�¢1Ser661 phosphorylation correlated with AKTSer473 and AKT substrate phosphorylation, Z-endoxifen at 5 ï�M uniquely blocked these effects and induced PKCÎ²1 protein degradation. siRNA-mediated PKCï�¢1 knockdown attenuated AKTSer473 phosphorylation, suggesting PKCÎ²1-mediated suppression of AKT signaling by Z-endoxifen. Further, Z-endoxifen at 5 ï�M replicates the pan-AKT inhibitor MK-2206 effects on apoptosis. These findings implicate PKCÎ²1 as a novel Z-endoxifen substrate responsible for suppressing AKT signaling and inducing apoptosis in breast cancer.

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