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

Mol Oncol. 2019 Dec;13(12):2646-2662. doi: 10.1002/1878-0261.12575. Epub 2019 Oct 24.

Abstract

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.

Keywords: c-Kit; cetuximab; colorectal cancer; invasion; omics; predictive biomarkers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism*
  • Humans
  • Proto-Oncogene Proteins c-kit / genetics
  • Proto-Oncogene Proteins c-kit / metabolism*
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Signal Transduction*
  • Tissue Inhibitor of Metalloproteinase-1 / genetics
  • Tissue Inhibitor of Metalloproteinase-1 / metabolism*

Substances

  • KRAS protein, human
  • TIMP1 protein, human
  • Tissue Inhibitor of Metalloproteinase-1
  • KIT protein, human
  • Proto-Oncogene Proteins c-kit
  • Proto-Oncogene Proteins p21(ras)