ABCG2-autophagy regulatory axis in cancer stem cells: implication in cancer metastasis, recurrence and chemotherapy resistance

Cancer stem cells (CSCs) play a key role in tumor initiation, metastasis, recurrence, and therapeutic resistance. ATP-binding cassette (ABC) transporter G2 (ABCG2) is a stem cell marker that not only regulates CSC properties but also by drug efflux contributes to chemoresistance. Autophagy is a catabolic process that supports CSC survival under stress. Emerging evidence suggests a regulatory relationship between ABCG2 and autophagy in maintaining the CSC phenotype. This review discusses the potential associations between different signaling pathways and transcription factors including hypoxia inducible factor-1 alpha (HIF-1α), nuclear factor erythroid 2–related factor 2 (Nrf2), estrogen receptor alpha (ERα), CCAAT/enhancer-binding protein β (C/EBPβ), NF-κB, protein kinase R-like ER kinase (PERK), peroxisome proliferator-activated receptor gamma (PPARγ), and Notch and induction of autophagy and ABCG2 expression in CSCs. Evidence is presented for how ABCG2-induced autophagy impacts metastasis, recurrence and drug resistance. Pharmacological strategies targeting ABCG2 and autophagy are examined for overcoming drug resistance. Combination therapies disrupting the ABCG2-autophagy axis may provide a novel approach for eliminating CSCs and improving treatment outcomes to reduce risk of drug resistance, tumor metastasis and recurrence. Future studies on elucidating the complex regulatory networks between these pathways offer opportunities to enhance current therapeutic approaches for controlling cancer progression.