TIMP-1 increases expression and phosphorylation of proteins associated with drug resistance in breast cancer cells

Omid Hekmat, Stephanie Munk, Louise Fogh, Rachita Yadav, Chiara Francavilla, Heiko Horn, Sidse Ornbjerg Wurtz, Anne-Sofie Schrohl, Britt Damsgaard, Maria Unni Romer, Kirstine C. Belling, Niels Frank Jensen, Irina Gromova, Dorte B Bekker-Jensen, Jose Manuel Matos Moreira, Lars Juhl Jensen, Ramneek Gupta, Ulrik Lademann, Nils Brunner, Jesper OlsenJan Stenvang

    Research output: Contribution to journalJournal articleResearchpeer-review

    Abstract

    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 hyper-phosphorylation 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.
    Original languageEnglish
    JournalJournal of Proteome Research
    Volume12
    Issue number9
    Pages (from-to)4136–4151
    ISSN1535-3907
    DOIs
    Publication statusPublished - 2013

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