Radioresistant breast cancer cells exhibit increased resistance to chemotherapy and enhanced invasive properties due to cancer stem cells

Ko, Young Shin; Jin, Hana; Lee, Jong Sil; Park, Sang Won; Chang, Ki Churl; Kang, Ki Mun; Jeong, Bae Kwon; Kim, Hye Jung

doi:10.3892/or.2018.6714

Cited by 37 publications

(72 citation statements)

References 32 publications

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“…In this study, several markers-CD44 and Oct-3/4 (octamer-binding transcription factor 3/4), βcatenin, and MMP-9-were chosen for RT resistance, for they were significantly increased after acquiring resistance to RT in previous study [9]. In addition, they are related to CSCs, cancer progression, and EMT.…”

Section: Pkal Significantly Inhibited Expression Of Stem Cell Markersmentioning

confidence: 99%

“…Our team previously established radio-resistant MDA-MB 231 human breast cancer cells (RT-R-MDA-MB 231 cells) which exhibit enhanced aggressiveness, and cancer stem cell features [9,10]. These cells also manifest epithelial-mesenchymal transition (EMT), a process by which epithelial cells gain migratory and invasive properties to become mesenchymal stem cells.…”

Section: Introductionmentioning

confidence: 99%

“…If pKAL exhibit significant anti-cancer effects on RT-R-MDA-MB-231 cells, pKAL-based phytotherapy will be an applicable and helpful option against resistance to RT or CT in breast cancer. In this study, we established RT-R-MDA-MB-231 cells following the previous protocol [9], determined whether pKAL would exhibit anti-cancer effects on the RT-R breast cancer cells, and further explored their molecular mechanisms by assessing the effects of pKAL on expressions of the proteins that were significantly higher expressed in RT-R-MDA-MB-231 cells than parental MDA-MB-231 cells, and assumed to be related to RT-resistance.…”

Section: Introductionmentioning

confidence: 99%

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Polyphenols Extracted from Artemisia annua L. Exhibit Anti-Cancer Effects on Radio-Resistant MDA-MB-231 Human Breast Cancer Cells by Suppressing Stem Cell Phenotype, β-Catenin, and MMP-9

Jung²,

Go³

et al. 2020

Molecules

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Artemisia annua L. has been reported to show anti-cancer activities. Here, we determined whether polyphenols extracted from Artemisia annua L. (pKAL) exhibit anti-cancer effects on radio-resistant MDA-MB-231 human breast cancer cells (RT-R-MDA-MB-231 cells), and further explored their molecular mechanisms. Cell viability assay and colony-forming assay revealed that pKAL inhibited cell proliferation on both parental and RT-R-MDA-MB-231 cells in a dose-dependent manner. The anti-proliferative effects of pKAL on RT-R-MDA-MB-231 cells were superior or similar to those on parental ones. Western blot analysis revealed that expressions of cluster of differentiation 44 (CD44) and Oct 3/4, matrix metalloproteinase-9 (MMP-9) and signal transducer and activator of transcription-3 (STAT-3) phosphorylation were significantly increased in RT-R-MDA-MB-231 cells compared to parental ones, suggesting that these proteins could be associated with RT resistance. pKAL inhibited the expression of CD44 and Oct 3/4 (CSC markers), and β-catenin and MMP-9 as well as STAT-3 phosphorylation of RT-R-MDA-MB-231. Regarding upstream signaling, the JNK or JAK2 inhibitor could inhibit STAT-3 activation in RT-R-MDA-MB-231 cells, but not augmented pKAL-induced anti-cancer effects. These findings suggest that c-Jun N-terminal kinase (JNK) or Janus kinase 2 (JAK2)/STAT3 signaling are not closely related to the anti-cancer effects of pKAL. In conclusion, this study suggests that pKAL exhibit anti-cancer effects on RT-R-MDA-MB-231 cells by suppressing CD44 and Oct 3/4, β-catenin and MMP-9, which appeared to be linked to RT resistance of RT-R-MDA-MB-231 cells.

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Section: Pkal Significantly Inhibited Expression Of Stem Cell Markersmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Polyphenols Extracted from Artemisia annua L. Exhibit Anti-Cancer Effects on Radio-Resistant MDA-MB-231 Human Breast Cancer Cells by Suppressing Stem Cell Phenotype, β-Catenin, and MMP-9

Jung²,

Go³

et al. 2020

Molecules

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“…Notch4 signaling promotes breast cancer cell survival in response to diverse treatment modalities [18][19][20] and is implicated in poor prognosis and high risk of relapse in breast cancer patients 21 . Notch4 signaling regulates susceptibility to cell death in human B cell acute lymphoblastic leukemia 1 , endothelial 3 , as well as cells of pancreatic origin 22 among others.…”

Section: Introductionmentioning

confidence: 99%

Nucleolar localization of the Notch4 intracellular domain underpins its regulation of the cellular response to genotoxic stressors

Saini

Sarin

2020

Cell Death Discov.

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Cell survival is one of the many cellular processes regulated by Notch family of proteins. A comparison of human breast cancer cell lines, which differ in the levels of endogenous Notch4, implicated the protein in regulating susceptibility to apoptosis triggered by genomic damage. In agreement with this observation, increased susceptibility to genotoxic damage was observed following siRNA ablations of Notch4 in two breast cancer cell lines. Further, overexpressing Notch4 intracellular domain (NIC4) tagged to GFP (NIC4-GFP), protected cells from apoptosis triggered by genotoxic drugs. In cells immune-stained for endogenous Notch4, protein was detected in the nucleolus and nucleoplasm, which was also confirmed by the co-localization of NIC4-GFP with RFP-tagged nucleolar proteins in breast cancer cells or the unrelated HEK cell line. Linking functional outcomes to nucleolar localization, NIC4-GFP protection from apoptosis, required the nucleolar proteins Nucleolin and Fibrillarin. Consistently, immunoprecipitation analysis revealed associations between nucleolar proteins-Nucleolin and Nucleophosmin-and Notch4. Microscopybased biophysical analysis of live cells showed that nucleolar and nucleoplasmic pools of NIC4-GFP are mobile, with some sequestration of nucleolar NIC4-GFP pools. A nucleolar excluded form, NIC4_3RA-GFP, generated by sitedirected mutagenesis of the nucleolar localization sequence in NIC4, could not protect from apoptosis triggered by genotoxic stressors. However, transcriptional activity or protection from apoptosis triggered by endoplasmic stress was comparable in cells expressing NIC4_3RA-GFP or NIC4-GFP. Together, the data show that nucleolar localization of NIC4 is critical for the regulation of genomic damage and may be uncoupled from its activities in the nucleoplasm. This study identifies intrinsic features of NIC4 that regulate signaling outcomes activated by the receptor by controlling its spatial localization.

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“…Radiotherapy is one of the most effective breast cancer treatment strategies which significantly improves the therapeutic outcome and survival of breast cancer patients (Moran et al, 2015;Bartelink et al, 2001;Fisher et al, 1995;Cun et al, 2013). Resistance to radiation represents one of the important challenges for breast cancer radiotherapy effectiveness including triple negative breast cancer (Ko et al, 2018;Qi et al,2017;He et al, 2018) which represent the most radio-resistant breast cancer (He et al, 2018;Kyndi et al, 2008). In the present study, found that TMPRSS4 inhibition increased TNBC cell radio-sensitivity ( Figure 1A, B, C) and improved the cell proliferation reduction mediated by IR ( Figure 2C).…”

Section: Discussionmentioning

confidence: 99%

Downregulation of TMPRSS4 Enhances Triple-Negative Breast Cancer Cell Radiosensitivity Through Cell Cycle and Cell Apoptosis Process Impairment

Assani

Segbo

et al. 2019

Asian Pac J Cancer Prev

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Background: Radioresistance remains a challenge for cancer radiotherapy. The present study aims to investigate the role of TMPRSS4 in triple negative breast cancer (TNBC) cell radiosensitivity. Materials and Methods: After transfection of MDA-MD-468 triple negative breast cancer cells line by using the lentivirus vector, the effect of TMPRSS4 down-regulation on TNBC radiosensitivity was evaluated by using cloning assay and CCK-8 assay. The CCK-8 assay was also used for performing cell proliferation analysis. Western blot was carried out to detect the expression of certain proteins related to cell cycle pathways (cyclin D1), cell apoptosis pathways (Bax, Bcl2, and Caspase3), DNA damage and DNA damage repair (TRF2, Ku80 , ˠH2AX). The cell cycle and cell apoptosis were also investigated using flow cytometer analysis. Results: TMPRSS4 expression was down-regulated in MDA-MB-468 cells which enhanced MDA-MB-468 cells radiosensitivity. TMPRSS4 silencing also improved IR induced cell proliferation ability reduction and promoted cell arrested at G2/M phase mediated by 6 Gy IR associated with cyclin D1 expression inhibition. Moreover, TMPRSS4 inhibition enhanced TNBC apoptosis induced by 6 Gy IR following by over-expression of (Bax, Caspase3) and down-regulation of Bcl2 as the pro-apoptotic and anti-apoptotic proteins, respectively. Otherwise, TMPRSS4 down-regulation increases DNA damage induced by 6 Gy IR and delays DNA damage repair respectively illustrated by downregulation of TRF2 and permanent increase of Ku80 and ˠH2AX expression at 1 h and 10 h post-IR. Conclusion: Down-regulation of TMPRSS4 increases triple negative breast cancer cell radiosensitivity and the use of TMPRSS4 inhibitor can be encouraged for improving radiotherapy effectiveness in TNBC radioresistant patients.

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Radioresistant breast cancer cells exhibit increased resistance to chemotherapy and enhanced invasive properties due to cancer stem cells

Cited by 37 publications

References 32 publications

Polyphenols Extracted from Artemisia annua L. Exhibit Anti-Cancer Effects on Radio-Resistant MDA-MB-231 Human Breast Cancer Cells by Suppressing Stem Cell Phenotype, β-Catenin, and MMP-9

Polyphenols Extracted from Artemisia annua L. Exhibit Anti-Cancer Effects on Radio-Resistant MDA-MB-231 Human Breast Cancer Cells by Suppressing Stem Cell Phenotype, β-Catenin, and MMP-9

Nucleolar localization of the Notch4 intracellular domain underpins its regulation of the cellular response to genotoxic stressors

Downregulation of TMPRSS4 Enhances Triple-Negative Breast Cancer Cell Radiosensitivity Through Cell Cycle and Cell Apoptosis Process Impairment

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