TY - JOUR

T1 - TIMP-1 increases expression and phosphorylation of proteins associated with drug resistance in breast cancer cells

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 - 2013/8/5

Y1 - 2013/8/5

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

VL - 12

SP - 4136

EP - 4151

JO - Journal of Proteome Research

JF - Journal of Proteome Research

SN - 1535-3893

IS - 9

ER -