Tankyrase Inhibitors Target Colorectal Cancer Stem Cells via AXIN-Dependent Downregulation of c-KIT Tyrosine Kinase.
Myung-Kyu JangTetsuo MashimaHiroyuki SeimiyaPublished in: Molecular cancer therapeutics (2020)
Cancer stem cells (CSC) constitute heterogeneous cell subpopulations of a tumor. Although targeting CSCs is important for cancer eradication, no clinically approved drugs that target CSCs have been established. Tankyrase poly(ADP-ribosyl)ates and destabilizes AXIN, a negative regulator of β-catenin, and promotes β-catenin signaling. Here, we report that tankyrase inhibitors downregulate c-KIT tyrosine kinase and inhibit the growth of CD44-positive colorectal CSCs. c-KIT expression in CD44-positive subpopulations of colorectal cancer COLO-320DM cells is associated with their tumor-initiating potential in vivo Tankyrase inhibitors downregulate c-KIT expression in established cell lines, such as COLO-320DM and DLD-1, and colorectal cancer patient-derived cells. These effects of tankyrase inhibitors are caused by reducing the recruitment of SP1 transcription factor to the c-KIT gene promoter and depend on AXIN2 stabilization but not β-catenin downregulation. Whereas c-KIT knockdown inhibits the growth of CD44-positive COLO-320DM cells, c-KIT overexpression in DLD-1 cells confers resistance to tankyrase inhibitors. Combination of a low-dose tankyrase inhibitor and irinotecan significantly inhibited the growth of COLO-320DM tumors in a mouse xenograft model. These observations suggest that tankyrase inhibitors target c-KIT-positive colorectal CSCs and provide a novel therapeutic strategy for cancer.
Keyphrases
- cancer stem cells
- tyrosine kinase
- induced apoptosis
- transcription factor
- cell proliferation
- cell cycle arrest
- low dose
- epidermal growth factor receptor
- signaling pathway
- epithelial mesenchymal transition
- endoplasmic reticulum stress
- dna methylation
- type diabetes
- gene expression
- stem cells
- adipose tissue
- single cell
- mesenchymal stem cells
- genome wide
- squamous cell
- binding protein
- risk assessment
- cancer therapy
- bone marrow
- genome wide identification
- lymph node metastasis