Cytotoxic Efficacy and Resistance Mechanism of a TRAIL and VEGFA-Peptide Fusion Protein in Colorectal Cancer Models.
Michal KopczynskiMalgorzata StatkiewiczMagdalena CybulskaUrszula KuklinskaKatarzyna Unrug-BielawskaZuzanna Sandowska-MarkiewiczAleksandra GrochowskaMarta GajewskaMaria KuleckaJerzy OstrowskiMichal MikulaPublished in: International journal of molecular sciences (2021)
TNF-related apoptosis-inducing ligand (TRAIL) is a type II transmembrane protein capable of selectively inducing apoptosis in cancer cells by binding to its cognate receptors. Here, we examined the anticancer efficacy of a recently developed chimeric AD-O51.4 protein, a TRAIL fused to the VEGFA-originating peptide. We tested AD-O51.4 protein activity against human colorectal cancer (CRC) models and investigated the resistance mechanism in the non-responsive CRC models. The quantitative comparison of apoptotic activity between AD-O51.4 and the native TRAIL in nine human colorectal cancer cell lines revealed dose-dependent toxicity in seven of them; the immunofluorescence-captured receptor abundance correlated with the extent of apoptosis. AD-O51.4 reduced the growth of CRC patient-derived xenografts (PDXs) with good efficacy. Cell lines that acquired AD-O51.4 resistance showed a significant decrease in surface TRAIL receptor expression and apoptosis-related proteins, including Caspase-8, HSP60, and p53. These results demonstrate the effectiveness of AD-O51.4 protein in CRC preclinical models and identify the potential mechanism underlying acquired resistance. Progression of AD-O51.4 to clinical trials is expected.
Keyphrases
- cell death
- oxidative stress
- cell cycle arrest
- endoplasmic reticulum stress
- clinical trial
- endothelial cells
- amino acid
- randomized controlled trial
- rheumatoid arthritis
- heat shock
- induced apoptosis
- systematic review
- cell therapy
- induced pluripotent stem cells
- stem cells
- high resolution
- mesenchymal stem cells
- cell proliferation
- single cell
- mass spectrometry
- heat stress
- microbial community
- open label