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Metallopeptidase in...
Metallopeptidase inhibitor 1 (TIMP-1) promotes receptor tyrosine kinase c-Kit signaling in colorectal cancer
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- Nordgaard, Cathrine (författare)
- University of Copenhagen
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- Doll, Sophia (författare)
- Max Planck Institute of Biochemistry
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- Matos, Ana Laura de Souza Almeida (författare)
- University of Copenhagen
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- Høeberg, Mikkel (författare)
- University of Copenhagen
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- Kazi, Julhash Uddin (författare)
- Lund University,Lunds universitet,Avdelningen för translationell cancerforskning,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Translational Cancer Research,Department of Laboratory Medicine,Faculty of Medicine
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- Friis, Stine (författare)
- University of Copenhagen
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- Stenvang, Jan (författare)
- University of Copenhagen
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- Rönnstrand, Lars (författare)
- Lund University,Lunds universitet,Molekylär cancerforskning,Forskargrupper vid Lunds universitet,Molecular Cancer Research,Lund University Research Groups,Skåne University Hospital
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- Mann, Matthias (författare)
- Max Planck Institute of Biochemistry,University of Copenhagen
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- Manuel Afonso Moreira, José (författare)
- University of Copenhagen
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(creator_code:org_t)
- 2019-10-24
- 2019
- Engelska 17 s.
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Ingår i: Molecular Oncology. - : Wiley. - 1574-7891 .- 1878-0261. ; 13:12, s. 2646-2662
- Relaterad länk:
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http://dx.doi.org/10... (free)
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https://febs.onlinel...
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https://lup.lub.lu.s...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Colorectal cancer (CRC) is the third most prevalent cancer worldwide causing an estimated 700 000 deaths annually. Different types of treatment are available for patients with advanced metastatic colorectal cancer, including targeted biological agents, such as cetuximab, a monoclonal antibody that targets EGFR. We have previously reported a study indicating multiple levels of interaction between metallopeptidase inhibitor 1 (TIMP-1) and the epidermal growth factor (EGF) signaling axis, which could explain how TIMP-1 levels can affect the antitumor effects of EGFR inhibitors. We also reported an association between TIMP-1-mediated cell invasive behavior and KRAS status. To gain insight into the molecular mechanisms underlying the effects of TIMP-1 in CRC, we examined by transcriptomics, proteomics, and kinase activity profiling a matched pair of isogenic human CRC isogenic DLD-1 CRC cell clones, bearing either an hemizygous KRAS wild-type allele or KRAS G13D mutant allele, exposed, or not, to TIMP-1. Omics analysis of the two cell lines identified the receptor tyrosine kinase c-Kit, a proto-oncogene that can modulate cell proliferation and invasion in CRC, as a target for TIMP-1. We found that exposure of DLD-1 CRC cells to exogenously added TIMP-1 promoted phosphorylation of c-Kit, indicative of a stimulatory effect of TIMP-1 on the c-Kit signaling axis. In addition, TIMP-1 inhibited c-Kit shedding in CRC cells grown in the presence of exogenous TIMP-1. Given the regulatory roles that c-Kit plays in cell proliferation and migration, and the realization that c-Kit is an important oncogene in CRC, it is likely that some of the biological effects of TIMP-1 overexpression in CRC may be exerted through its effect on c-Kit signaling.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Nyckelord
- c-Kit
- cetuximab
- colorectal cancer
- invasion
- omics
- predictive biomarkers
Publikations- och innehållstyp
- art (ämneskategori)
- ref (ämneskategori)
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