Aryl hydrocarbon receptor counteracts pharmacological efficacy of doxorubicin via enhanced AKR1C3 expression in triple negative breast cancer cells

Yamashita, Naoya; Kanno, Yuichiro; Saito, Nagahito; Terai, Kensuke; Sanada, Noriko; Kizu, Ryoichi; Hiruta, Nobuyuki; Park, Youngjin; Bujo, Hideaki; Nemoto, Kiyomitsu

doi:10.1016/j.bbrc.2019.06.119

Cited by 27 publications

(17 citation statements)

References 25 publications

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“…Cytotoxic drugs often induce DNA damage and cancer cell apoptosis leading to death ( 9 ). Doxorubicin, a known is a commonly chemotherapeutic for BC ( 10 , 11 ), kills cancer cells by inducing DNA-crosslinking damage, which if not properly repaired, leads to double strand breaks and ultimate cellular death ( 12 , 13 ). Evidence showed that doxorubicin had anti-cancer effect at a higher concentration which produce cardiotoxicity ( 14 ).…”

Section: Introductionmentioning

confidence: 99%

RETRACTED: Emodin Interferes With AKT1-Mediated DNA Damage and Decreases Resistance of Breast Cancer Cells to Doxorubicin

Zhao

Zhang

et al. 2021

Front. Oncol.

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Doxorubicin (DOX) is a cytotoxic drug used for the treatment of breast cancer (BC). However, the rapid emergence of resistance toward doxorubicin threatens its clinical application, thus the need for combination therapy. Here, we interrogate the role of Emodin, a chemical compound with tumor inhibitory properties, in the resistance of BC to Doxorubicin. We first evaluated the efficacy of Emodin in the treatment of BC cells. We then used γH2A to examine doxorubicin-induced DNA damage in BC cells, with or without Emodin. Data from CCK-8, flow cytometry, and tumor xenograft assays showed that Emodin suppresses the growth of BC cells. Further, we demonstrated that Emodin enhances γH2A levels in BC cells. Moreover, bioinformatics analysis and western blot assays indicated that Emodin down-regulates the AKT1 expression, and marginally decreases the levels of DNA damage proteins (XRCC1, PARP1, and RAD51) as well as increased p53 expression in BC cells. Taken together, our data demonstrates that Emodin affects cell proliferation, and DNA damage pathways in BC cells, thus increasing the sensitivity of BC cells to doxorubicin. Besides, we confirmed that Emodin confers sensitization of BC to doxorubicin through AKT1-mediated DNA.

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Section: Introductionmentioning

confidence: 99%

RETRACTED: Emodin Interferes With AKT1-Mediated DNA Damage and Decreases Resistance of Breast Cancer Cells to Doxorubicin

Zhao

Zhang

et al. 2021

Front. Oncol.

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“…Assuming an average population of 10 DTCs per million BM cells [ 33 ], this also suggests that the Parsortix platform was able to perform at least a 500-fold enrichment of DTCs from BM. Moreover, the cluster of EpCAM enriched cells were also enriched for several other genes of clinical interest including APOC1 , a biomarker of tumor progression [ 34 ], ALDH1A1 , a marker of tumor cell “stemness” [ 35 ], and AKR1C3 , a marker of doxorubicin resistance [ 36 ]. Thus, viable cell enrichment with the microfluidic platform not only allowed detection of DTC populations but as shown by this example, allowed for the delineation of independent DTC populations (EpCAM positive and EpCAM negative) whose molecular phenotypes may have distinct, additive, or synergistic consequences for treatment and monitoring of DTC populations to mitigate metastatic progression.…”

Section: Resultsmentioning

confidence: 99%

A microfluidic-based filtration system to enrich for bone marrow disseminated tumor cells from breast cancer patients

Pillai

Siddappa

et al. 2021

PLoS ONE

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Disseminated tumors cells (DTCs) present in the bone marrow (BM) are believed to be the progenitors of distant metastatic spread, a major cause of mortality in breast cancer patients. To better understand the behavior and therapeutic vulnerabilities of these rare cell populations, unbiased methods for selective cell enrichment are required. In this study, we have evaluated a microfluidic-based filtration system (ParsortixR, Angle PLC), previously demonstrated for use in circulating tumor cell (CTC) capture, to capture BM DTCs. Performance using BM samples was also compared directly to enrichment of CTCs in the peripheral blood (PB) from both metastatic and non-metastatic breast cancer patients. Although the non-specific capture of BM immune cells was significant, the device could routinely achieve significant cytoreduction of BM and PB WBCs and at least 1,000-fold enrichment of DTCs, based on labeled tumor cell spike-in experiments. Detection of previously characterized DTC-associated gene expression biomarkers was greatly enhanced by the enrichment method, as demonstrated by droplet digital PCR assay. Cells eluted from the device were viable and suitable for single cell RNA sequencing experiments. DTCs in enriched BM samples comprised up to 5% of the total cell population, allowing for effective single cell and population-based transcriptional profiling of these rare cells. Use of the Parsortix instrument will be an effective approach to enrich for rare BM DTCs in order to better understand their diverse molecular phenotypes and develop approaches to eradicate these cells to prevent distant disease development in breast cancer patients.

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“…Similarly, Yamashita et al demonstrated that AhR counteracts the efficacy of doxorubicin (DOX) via enhanced AKR1C3 expression in TNBC through extensive metabolization of the drug. The cytotoxic effect of DOX was more pronounced in Ahr −/− MDA-MB 231 TNBC cells [107].…”

Section: Ahr As a Sensitizer Of Cancer Therapiesmentioning

confidence: 92%

AhR and Cancer: from Gene Profiling to Targeted Therapy

Paris

Tardif

Galibert

et al. 2020

Preprint

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The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that has been shown to be an essential regulator of a broad spectrum of biological activities required for maintaining the body's vital functions. AhR also plays a critical role in tumorigenesis. Its role in cancer is complex, encompassing both pro- and anti-tumorigenic activities. Its level of expression and activity are specific to each tumor and patient, increasing the difficulty of understanding the activating or inhibiting roles of AhR ligands. We explored the role of AhR in tumor cell lines and patients using genomic data sets and discuss the extent to which AhR can be considered as a therapeutic target.

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Aryl hydrocarbon receptor counteracts pharmacological efficacy of doxorubicin via enhanced AKR1C3 expression in triple negative breast cancer cells

Cited by 27 publications

References 25 publications

RETRACTED: Emodin Interferes With AKT1-Mediated DNA Damage and Decreases Resistance of Breast Cancer Cells to Doxorubicin

RETRACTED: Emodin Interferes With AKT1-Mediated DNA Damage and Decreases Resistance of Breast Cancer Cells to Doxorubicin

A microfluidic-based filtration system to enrich for bone marrow disseminated tumor cells from breast cancer patients

AhR and Cancer: from Gene Profiling to Targeted Therapy

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