Tissue inhibitor of metalloproteinase-1 decreased chemosensitivity of MDA-435 breast cancer cells to chemotherapeutic drugs through the PI3K/AKT/NF-кB pathway

Fu, Ziyi; Lv, Jinghuan; Ma, Chao; Yang, Dan; Wang, T.

doi:10.1016/j.biopha.2011.02.004

Cited by 41 publications

(32 citation statements)

References 23 publications

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“…Transcription of proinflammatory mediators, such as cytokines and chemokines (i.e., IL-8), can be regulated by nuclear factor-кB (NF-кB) [17,18]. Activation of NF-кB in immune cells up-regulates the expression of cytokines and growth factors that are essential to the immune response and that contribute to inflammation [19].…”

Section: Introductionmentioning

confidence: 99%

Allyl methyl disulfide inhibits IL-8 and IP-10 secretion in intestinal epithelial cells via the NF-кB signaling pathway

Zhang

Wang

Zhang

et al. 2015

International Immunopharmacology

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Section: Introductionmentioning

confidence: 99%

Allyl methyl disulfide inhibits IL-8 and IP-10 secretion in intestinal epithelial cells via the NF-кB signaling pathway

Zhang

Wang

Zhang

et al. 2015

International Immunopharmacology

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“…TIMP-1 has been shown to have anti-apoptotic and proliferative properties [18,19], and the absence of TIMP-1 has been associated with increased chemotherapy sensitivity [20,21]. Fu et al showed that overexpression of TIMP-1 significantly decreased the sensitivity of MDA-435 breast cancer cells to epirubicin and paclitaxel [22]. Further, Schrohl et al selected a group of 525 premenopausal patients who had received either CMF, anthracycline-based or no adjuvant chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

TIMP-1 in combination with HER2 and TOP2A for prediction of benefit from adjuvant anthracyclines in high-risk breast cancer patients

Hertel

Ejlertsen

et al. 2011

Breast Cancer Res Treat

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HER2 amplification, TOP2A aberrations, and absence of tissue inhibitor of metalloproteinase (TIMP-1) expression in breast carcinomas have been shown to be associated with incremental benefit from anthracycline-containing adjuvant chemotherapy, and this study was undertaken to validate these findings in a similar, but independent, randomized clinical trial. TIMP-1 was examined by immunohistochemistry in archival tumor tissue from 403 of 716 premenopausal high-risk patients with known HER2 and TOP2A status who were randomized to cyclophosphamide, epirubicin, and fluorouracil (CEF) or cyclophosphamide, methotrexate, and fluorouracil (CMF) in the MA.5 trial. Ninety-eight (24%) patients had no TIMP-1 staining of tumor cells, 27% were HER2 amplified, and 18% were TOP2A aberrant. Forty-four percentage was classified as HT responsive (HER2 amplified and/or TIMP-1 negative) and 37% as 2T responsive (TOP2A aberrant and/or TIMP-1 negative). There was no heterogeneity in treatment effect of CEF versus CMF according to TIMP-1. In HT-responsive patients, CEF was superior to CMF with an improved RFS (adjusted HR, 0.64; 95% CI, 0.42-0.97), but this was not significant for OS (adjusted HR, 0.66; 95% CI, 0.42-1.04). A significant HT profile versus treatment interaction was detected for OS (P = 0.03). In 2T-responsive patients, CEF seemed to improve RFS compared to CMF (adjusted HR, 0.67; 95% CI, 0.43-1.03) and improved OS (adjusted HR, 0.58; 95% CI, 0.36-0.93). A significant 2T profile versus treatment interaction was detected for OS (P = 0.01). With this study, we validate a more substantial reduction in mortality by CEF compared to CMF in patients with an HT- or 2T-responsive profile; however, we could not show a similarly significant reduction in RFS events, where a benefit of CEF over CMF was found irrespective of TIMP-1 status. Further studies are necessary before the HT and 2T profiles may be used to direct the use of anthracyclines.

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“…We mapped the most upregulated proteins and phospho-proteins to functional classes using IPA and found enrichment for processes that TIMP-1 is believed to be involved in, for example, apoptosis, cell cycle, transcription factors, DNA repair, drug transport, and drug resistance/sensitivity. [7][8][9][10][11]28,59 It is particularly interesting that all the identified topoisomerases were either hyper-phosphorylated or overexpressed since this may explain why previous studies found high TIMP-1 levels in tumor or plasma to be associated with decreased benefit from topoisomerase inhibitor containing chemotherapy, 12−15 as both topoisomerase 1 and 2 activity is positively dependent on phosphorylation. 60−62 It is therefore intriguing to speculate that increased expression levels and phosphorylation status of topoisomerases may cause the chemotherapy resistance phenotype.…”

Section: ■ Discussionmentioning

confidence: 99%

TIMP-1 Increases Expression and Phosphorylation of Proteins Associated with Drug Resistance in Breast Cancer Cells

Hekmat

Munk

Fogh³

et al. 2013

J. Proteome Res.

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Tissue inhibitor of metalloproteinase 1 (TIMP-1) is a protein with a potential biological role in drug resistance. To elucidate the unknown molecular mechanisms underlying the association between high TIMP-1 levels and increased chemotherapy resistance, we employed SILAC-based quantitative mass spectrometry to analyze global proteome and phosphoproteome differences of MCF-7 breast cancer cells expressing high or low levels of TIMP-1. In TIMP-1 high expressing cells, 312 proteins and 452 phosphorylation sites were up-regulated. Among these were the cancer drug targets topoisomerase 1, 2A, and 2B, which may explain the resistance phenotype to topoisomerase inhibitors that was observed in cells with high TIMP-1 levels. Pathway analysis showed an enrichment of proteins from functional categories such as apoptosis, cell cycle, DNA repair, transcription factors, drug targets and proteins associated with drug resistance or sensitivity, and drug transportation. The NetworKIN algorithm predicted the protein kinases CK2a, CDK1, PLK1, and ATM as likely candidates involved in the hyperphosphorylation of the topoisomerases. Up-regulation of protein and/or phosphorylation levels of topoisomerases in TIMP-1 high expressing cells may be part of the mechanisms by which TIMP-1 confers resistance to treatment with the widely used topoisomerase inhibitors in breast and colorectal cancer.

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Tissue inhibitor of metalloproteinase-1 decreased chemosensitivity of MDA-435 breast cancer cells to chemotherapeutic drugs through the PI3K/AKT/NF-кB pathway

Cited by 41 publications

References 23 publications

Allyl methyl disulfide inhibits IL-8 and IP-10 secretion in intestinal epithelial cells via the NF-кB signaling pathway

Allyl methyl disulfide inhibits IL-8 and IP-10 secretion in intestinal epithelial cells via the NF-кB signaling pathway

TIMP-1 in combination with HER2 and TOP2A for prediction of benefit from adjuvant anthracyclines in high-risk breast cancer patients

TIMP-1 Increases Expression and Phosphorylation of Proteins Associated with Drug Resistance in Breast Cancer Cells

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