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The stem cell gene ABCB5 mediates cancer resistance to apoptosis

ABSTRACT: Cancer stem cells (CSC) responsible for disease progression and therapeutic resistance have been identified in several human malignancies, including colorectal cancer (CRC). However, the molecular mechanisms through which CSC drive tumor growth are incompletely understood. ABCB5, a member of the ATP-binding cassette superfamily of active transporters, serves as a CSC-specific multidrug resistance mechanism in diverse human malignancies. Additionally, ABCB5 has recently been demonstrated to function as an anti-apoptotic gene in tissue-specific non-malignant stem cells. Here we demonstrate that ABCB5 also serves an anti-apoptotic role required for CSC maintenance in human cancer. Targeted inhibition of ABCB5, previously shown to be preferentially expressed on CD133-positive CRC stem cells, induced tumor cell apoptosis in vitro and in vivo and inhibited human CRC growth in NSG recipient mice. Mechanistically, ABCB5-positive tumor cell ablation through monoclonal antibody-mediated blockade or shRNA-mediated gene knockdown resulted in diminished production of the receptor tyrosine kinase AXL, a pro-tumorigenic molecule identified herein to be preferentially produced by CRC stem cells. Restoration of AXL expression through gene transfection in ABCB5 knockdown tumors partially restored tumor growth, demonstrating that ABCB5-positive CRC stem cells drive tumorigenicity at least in part through production of AXL. Our results establish a novel anti-apoptotic function of ABCB5 in human cancer and indicate that targeted blockade of ABCB5 represents a novel strategy for CSC eradication, independent of its previously established function as a multidrug resistance mediator.

ORGANISM(S): Homo sapiens

PROVIDER: GSE71670 | GEO | 2018/08/01

REPOSITORIES: GEO

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