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 Ørnbjerg Würtz; Anne-Sofie Schrohl; Britt Damsgaard; Maria Unni Romer; Kirstine Belling; Niels Frank Jensen; Irina Gromova; Dorte B Bekker-Jensen; José Moreira; Lars Juhl Jensen; Ramneek Gupta; Ulrik Axel Lademann; Nils Brünner; Jesper Velgaard Olsen; Jan Stenvang

doi:10.1021/pr400457u

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 Ørnbjerg Würtz, Anne-Sofie Schrohl, Britt Damsgaard, Maria Unni Romer, Kirstine Belling, Niels Frank Jensen, Irina Gromova, Dorte B Bekker-Jensen, José Moreira, Lars Juhl Jensen, Ramneek Gupta, Ulrik Axel Lademann, Nils Brünner, Jesper Velgaard OlsenJan Stenvang

24 Citations (Scopus)

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 language	English
Journal	Journal of Proteome Research
Volume	12
Issue number	9
Pages (from-to)	4136-4151
Number of pages	16
ISSN	1535-3893
DOIs	https://doi.org/10.1021/pr400457u
Publication status	Published - 6 Sept 2013

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Hekmat, O., Munk, S., Fogh, L., Yadav, R., Francavilla, C., Horn, H., Würtz, S. Ø., Schrohl, A-S., Damsgaard, B., Romer, M. U., Belling, K., Jensen, N. F., Gromova, I., Bekker-Jensen, D. B., Moreira, J., Jensen, L. J., Gupta, R., Lademann, U. A., Brünner, N., ... Stenvang, J. (2013). TIMP-1 increases expression and phosphorylation of proteins associated with drug resistance in breast cancer cells. Journal of Proteome Research, 12(9), 4136-4151. https://doi.org/10.1021/pr400457u

Hekmat, O, Munk, S, Fogh, L, Yadav, R, Francavilla, C, Horn, H, Würtz, SØ, Schrohl, A-S, Damsgaard, B, Romer, MU, Belling, K, Jensen, NF, Gromova, I, Bekker-Jensen, DB, Moreira, J , Jensen, LJ, Gupta, R, Lademann, UA, Brünner, N , Olsen, JV & Stenvang, J 2013, 'TIMP-1 increases expression and phosphorylation of proteins associated with drug resistance in breast cancer cells', Journal of Proteome Research, vol. 12, no. 9, pp. 4136-4151. https://doi.org/10.1021/pr400457u

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

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.",

author = "Omid Hekmat and Stephanie Munk and Louise Fogh and Rachita Yadav and Chiara Francavilla and Heiko Horn and W{\"u}rtz, {Sidse {\O}rnbjerg} and Anne-Sofie Schrohl and Britt Damsgaard and Romer, {Maria Unni} and Kirstine Belling and Jensen, {Niels Frank} and Irina Gromova and Bekker-Jensen, {Dorte B} and Jos{\'e} Moreira and Jensen, {Lars Juhl} and Ramneek Gupta and Lademann, {Ulrik Axel} and Nils Br{\"u}nner and Olsen, {Jesper Velgaard} and Jan Stenvang",

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AU - Hekmat, Omid

AU - Munk, Stephanie

AU - Fogh, Louise

AU - Yadav, Rachita

AU - Francavilla, Chiara

AU - Horn, Heiko

AU - Würtz, Sidse Ørnbjerg

AU - Schrohl, Anne-Sofie

AU - Damsgaard, Britt

AU - Romer, Maria Unni

AU - Belling, Kirstine

AU - Jensen, Niels Frank

AU - Gromova, Irina

AU - Bekker-Jensen, Dorte B

AU - Moreira, José

AU - Jensen, Lars Juhl

AU - Gupta, Ramneek

AU - Lademann, Ulrik Axel

AU - Brünner, Nils

AU - Olsen, Jesper Velgaard

AU - Stenvang, Jan

PY - 2013/9/6

Y1 - 2013/9/6

N2 - 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.

AB - 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.

U2 - 10.1021/pr400457u

DO - 10.1021/pr400457u

M3 - Journal article

C2 - 23909892

SN - 1535-3893

VL - 12

SP - 4136

EP - 4151

JO - Journal of Proteome Research

JF - Journal of Proteome Research

IS - 9

ER -

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

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