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Abstract
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.
Highlights
Colorectal cancer is the fourth leading cause of cancer-related deaths in the world
CD44-positive COLO-320DM cells are characterized as a colorectal cancer stem cells (CSC)
We used a colorectal cancer cell line that contains a cell subpopulation with CSC properties to screen for drugs that preferentially target the CSC fraction
Summary
Colorectal cancer is the fourth leading cause of cancer-related deaths in the world. For the treatment of recurrent and metastatic colorectal cancer, conventional cytotoxic drugs and molecularly targeted drugs are used as standard therapies. Complete eradication of colorectal cancer is hampered by the intrinsic and acquired drug resistance of these tumors. Tumor tissues contain heterogeneous cancer cell populations, which include subpopulations called cancer stem cells (CSC) that exhibit highly tumorigenic potential. CSCs are self-renewable and resistant to chemotherapy and radiotherapy, causing relapse of the disease. Previous studies have identified the presence of CSCs in various types of cancers, including leukemia, breast, brain, prostate, pancreatic, stomach, and colorectal cancers [1]. Subpopulations of cancer cells that express stem cell–related cell surface antigens, such as CD44 [2] and Lgr5 [3], possess CSC-like properties. The development of therapeutic drugs that preferentially attack CSCs is required for the complete eradication of cancer. Several candidate compounds have been proposed as potential agents to target CSCs, such as napabucasin (BBI 608) targeting the STAT3 signaling pathway [4] and OTS167, a selective inhibitor of maternal embryonic leucine zipper kinase [5], and are under clinical
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