β-catenin mediates growth defects induced by centrosome loss in a subset of APC mutant colorectal cancer independently of p53.
Mohamed BourmoumNikolina RadulovichAmit SharmaJohnny M TkachMing Sound TsaoLaurence PelletierPublished in: PloS one (2024)
Colorectal cancer is the third most common cancer and the second leading cause of cancer-related deaths worldwide. The centrosome is the main microtubule-organizing center in animal cells and centrosome amplification is a hallmark of cancer cells. To investigate the importance of centrosomes in colorectal cancer, we induced centrosome loss in normal and cancer human-derived colorectal organoids using centrinone B, a Polo-like kinase 4 (Plk4) inhibitor. We show that centrosome loss represses human normal colorectal organoid growth in a p53-dependent manner in accordance with previous studies in cell models. However, cancer colorectal organoid lines exhibited different sensitivities to centrosome loss independently of p53. Centrinone-induced cancer organoid growth defect/death positively correlated with a loss of function mutation in the APC gene, suggesting a causal role of the hyperactive WNT pathway. Consistent with this notion, β-catenin inhibition using XAV939 or ICG-001 partially prevented centrinone-induced death and rescued the growth two APC-mutant organoid lines tested. Our study reveals a novel role for canonical WNT signaling in regulating centrosome loss-induced growth defect/death in a subset of APC-mutant colorectal cancer independently of the classical p53 pathway.
Keyphrases
- papillary thyroid
- high glucose
- endothelial cells
- diabetic rats
- squamous cell
- cell proliferation
- epithelial mesenchymal transition
- stem cells
- single cell
- induced apoptosis
- squamous cell carcinoma
- dna methylation
- childhood cancer
- genome wide
- cell therapy
- photodynamic therapy
- bone marrow
- fluorescence imaging
- pluripotent stem cells