Tankyrase Inhibitors Target Colorectal Cancer Stem Cells via AXIN-Dependent Downregulation of c-KIT Tyrosine Kinase
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- Myung-Kyu Jang
- 1Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
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- Tetsuo Mashima
- 1Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
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- Hiroyuki Seimiya
- 1Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
Description
<jats:title>Abstract</jats:title> <jats:p>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.</jats:p>
Journal
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- Molecular Cancer Therapeutics
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Molecular Cancer Therapeutics 19 (3), 765-776, 2020-03-01
American Association for Cancer Research (AACR)
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Keywords
- Mice, Inbred BALB C
- Tankyrases
- Mice, Nude
- Antineoplastic Agents
- Apoptosis
- Mice, SCID
- Xenograft Model Antitumor Assays
- Gene Expression Regulation, Neoplastic
- Mice
- Proto-Oncogene Proteins c-kit
- Axin Protein
- Mice, Inbred NOD
- Neoplastic Stem Cells
- Tumor Cells, Cultured
- Animals
- Humans
- Female
- Enzyme Inhibitors
- Colorectal Neoplasms
- Wnt Signaling Pathway
- Cell Proliferation
Details 詳細情報について
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- CRID
- 1360849946322737536
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- ISSN
- 15388514
- 15357163
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- PubMed
- 31907221
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- Article Type
- journal article
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- Data Source
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- Crossref
- KAKEN
- OpenAIRE
