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 -