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Published on: January 22, 2018
Antitumor activity of cell-permeable RUNX3 protein in gastric cancer cells
Junghee Lim1, Tam Duong, Nga Do
1ProCell R&D Institute, ProCell Therapeutics, Inc., Seoul, Korea.
Purpose:
Gastric cancer is a leading cause of cancer death worldwide. Limited therapeutic options highlight the need to understand the molecular changes responsible for the disease and to develop therapies based on this understanding. The goal of this study was to develop cell-permeable (CP-) forms of the RUNT-related transcription factor 3, RUNX3-a candidate tumor suppressor implicated in gastric and other epithelial cancers-to study the therapeutic potential of RUNX3 in the treatment of gastric cancer.
Experimental Design:
We developed novel macromolecule transduction domains (MTD) which were tested for the ability to promote protein uptake by mammalian cells and tissues and used to deliver of biologically active RUNX3 into human gastric cancer cells. The therapeutic potential CP-RUNX3 was tested in the NCI-N87 human tumor xenograft animal model.
Results:
RUNX3 fusion proteins, HM(57)R and HM(85)R, containing hydrophobic MTDs enter gastric cancer cells and suppress cell phenotypes (e.g., cell-cycle progression, wounded monolayer healing, and survival) and induce changes in biomarker expression (e.g., p21(Waf1) and VEGF) consistent with previously described effects of RUNX3 on TGF-β signaling. CP-RUNX3 also suppressed the growth of subcutaneous human gastric tumor xenografts. The therapeutic response was comparable with studies augmenting RUNX3 gene expression in tumor cell lines; however, the protein was most active when administered locally, rather than systemically (i.e., intravenously).
Conclusions:
These results provide further evidence that RUNX3 can function as a tumor suppressor and suggest that practical methods to augment RUNX3 function could be useful in treating of some types of gastric cancer.
Insights
Researchers developed cell-permeable RUNX3 (CP-RUNX3) proteins to suppress gastric cancer growth. CP-RUNX3 demonstrated therapeutic potential by inhibiting tumor xenografts, suggesting a new treatment strategy for gastric cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Gastric cancer is a major global cause of cancer mortality.
- Limited therapeutic options necessitate understanding molecular drivers and developing targeted therapies.
- RUNX3, a RUNT-related transcription factor 3, is a potential tumor suppressor in epithelial cancers, including gastric cancer.
Purpose of the Study:
- To develop cell-permeable (CP-) forms of RUNX3.
- To investigate the therapeutic potential of CP-RUNX3 in gastric cancer treatment.
- To utilize novel macromolecule transduction domains (MTDs) for delivering RUNX3 into cancer cells.
Main Methods:
- Development and testing of novel MTDs for protein uptake.
- Delivery of biologically active RUNX3 into human gastric cancer cells.
- Evaluation of CP-RUNX3 therapeutic potential in a human gastric tumor xenograft model.
Main Results:
- RUNX3 fusion proteins (HM(57)R, HM(85)R) with MTDs entered gastric cancer cells.
- CP-RUNX3 suppressed cancer cell phenotypes (cell-cycle, healing, survival) and altered biomarker expression (p21(Waf1), VEGF).
- CP-RUNX3 inhibited tumor xenograft growth, with local administration being more effective than systemic.
Conclusions:
- RUNX3 functions as a tumor suppressor in gastric cancer.
- Augmenting RUNX3 function presents a potential therapeutic strategy for gastric cancer.
- Cell-permeable RUNX3 offers a novel approach for delivering this tumor suppressor protein.
