Abstract
The adenosine triphosphate (ATP)-binding cassette efflux transporter G2 (ABCG2) was originally discovered in a multidrug-resistant breast cancer cell line. Studies in the past have expanded the understanding of its role in physiology, disease pathology and drug resistance. With a widely distributed expression across different cell types, ABCG2 plays a central role in ATP-dependent efflux of a vast range of endogenous and exogenous molecules, thereby maintaining cellular homeostasis and providing tissue protection against xenobiotic insults. However, ABCG2 expression is subjected to alterations under various pathophysiological conditions such as inflammation, infection, tissue injury, disease pathology and in response to xenobiotics and endobiotics. These changes may interfere with the bioavailability of therapeutic substrate drugs conferring drug resistance and in certain cases worsen the pathophysiological state aggravating its severity. Considering the crucial role of ABCG2 in normal physiology, therapeutic interventions directly targeting the transporter function may produce serious side effects. Therefore, modulation of transporter regulation instead of inhibiting the transporter itself will allow subtle changes in ABCG2 activity. This requires a thorough comprehension of diverse factors and complex signaling pathways (Kinases, Wnt/β-catenin, Sonic hedgehog) operating at multiple regulatory levels dictating ABCG2 expression and activity. This review features a background on the physiological role of transporter, factors that modulate ABCG2 levels and highlights various signaling pathways, molecular mechanisms and genetic polymorphisms in ABCG2 regulation. This understanding will aid in identifying potential molecular targets for therapeutic interventions to overcome ABCG2-mediated multidrug resistance (MDR) and to manage ABCG2-related pathophysiology.
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References
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Acknowledgements
This work was supported by the Council of Scientific and Industrial Research (CSIR) under Grant OLP1154. We are thankful to the Director, CSIR- Institute of Genomics and Integrative Biology (IGIB), Dr. Anurag Agrawal, for his scientific vision and support. SK (Samiksha Kukal) acknowledge Department of Biotechnology (DBT) and CSIR, Govt. of India, DG and MKM acknowledge Indian Council of Medical Research (ICMR), Govt. of India, SB, PRP and NK acknowledge CSIR, Govt. of India and CR acknowledges University Grants Commission (UGC), Govt. of India, for their financial assistance. We thank the anonymous reviewers for their helpful suggestions in improving the manuscript. All authors have read and approve the journal’s authorship agreement and policy on disclosure of potential conflicts of interest. The authors declare no conflicts of interest. No sources of editorial support were used in the preparation of this manuscript.
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This work was supported by Council of Scientific and Industrial Research (CSIR) under Grant OLP1154.
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RK devised the concept of the review, reviewed the manuscript and supervised the overall work till final manuscript preparation. SK (Samiksha Kukal) did the literature search, reviewed articles and prepared the original draft. SB and PS helped with the literature search and preparation of tables. DG and CR reviewed the manuscript. SK (Samiksha Kukal), DG and CR edited the manuscript. SK (Samiksha Kukal) and DG designed and prepared the figures. MKM helped with the designing of figures. RK, DG, CR, PRP, NK, GKG, SK (Shrikant Kukreti) and LS finally revised the figures, tables and the whole manuscript. All the authors read and approved the final manuscript.
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Kukal, S., Guin, D., Rawat, C. et al. Multidrug efflux transporter ABCG2: expression and regulation. Cell. Mol. Life Sci. 78, 6887–6939 (2021). https://doi.org/10.1007/s00018-021-03901-y
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DOI: https://doi.org/10.1007/s00018-021-03901-y