TY - JOUR

T1 - Metallopeptidase Inhibitor 1 (TIMP-1) promotes receptor tyrosine kinase c-Kit signaling in colorectal cancer

AU - Nordgaard, Cathrine

AU - Doll, Sophia

AU - Matos, Ana Laura de Souza Almeida

AU - Høeberg, Mikkel

AU - Kazi, Julhash Uddin

AU - Friis, Stine

AU - Stenvang, Jan

AU - Rönnstrand, Lars

AU - Mann, Matthias

AU - Moreira, José Manuel Afonso

PY - 2019

Y1 - 2019

N2 - Colorectal cancer (CRC) is the third most prevalent cancer worldwide causing an estimated 700000 deaths annually. Different types of treatment are available for patients with advanced metastatic colorectal cancer (mCRC), 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 anti-tumor 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, and 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.

AB - Colorectal cancer (CRC) is the third most prevalent cancer worldwide causing an estimated 700000 deaths annually. Different types of treatment are available for patients with advanced metastatic colorectal cancer (mCRC), 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 anti-tumor 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, and 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.

U2 - 10.1002/1878-0261.12575

DO - 10.1002/1878-0261.12575

M3 - Journal article

C2 - 31545548

VL - 13

SP - 2646

EP - 2662

JO - Molecular Oncology

JF - Molecular Oncology

SN - 1574-7891

IS - 12

ER -