The Stem Cell Marker Bcrp/ABCG2 Enhances Hypoxic Cell Survival through Interactions with Heme*
By Partha Krishnamurthy, D. Ross, T. Nakanishi, Kim Bailey-Dell, Sheng Zhou, K. Mercer, B. Sarkadi, B. Sorrentino, J. Schuetz. Journal of Biological Chemistry, 2004
688 citations recorded by the source corpus.
Our studies demonstrate that the ABC transporter and marker of stem and progenitor cells known as the breast cancer resistance protein (BCRP or ABCG2) confers a strong survival advantage under hypoxic conditions. We show that, under hypoxia, progenitor cells from Bcrp–/–mice have a reduced ability to form colonies as compared with progenitor cells from Bcrp+/+ mice. Blocking BCRP function in Bcrp+/+ progenitor cells markedly reduces survival under hypoxic conditions. However, blocking heme biosynthesis reverses the hypoxic susceptibility of Bcrp–/– progenitor cells, a finding that indicates that heme molecules (i.e. porphyrins) are detrimental to Bcrp–/– cells under hypoxia. BCRP specifically binds heme, and cells lacking BCRP accumulate porphyrins. Finally, Bcrp expression is up-regulated by hypoxia, and we demonstrate that this up-regulation involves the hypoxia-inducible transcription factor complex HIF-1. Collectively, our findings suggest that cells can, upon hypoxic demand, use BCRP to reduce heme or porphyrin accumulation, which can be detrimental to cells. Our findings have implications for the survival of stem cells and tumor cells in hypoxic environments.
Subfields: Molecular Biology, Oncology
View Paper: https://www.semanticscholar.org/paper/1ba5f7a33567cf1472d13b387474148541f1d8f3
How researchers see this paper
The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.
In Molecular Biology
In Oncology
Citations in the corpus
- Mechanisms of cell protection by heme oxygenase-1. (2010, background): “Expression of Abcg2/Bcrp is induced under hypoxia (178, 184) and affords cytoprotection against hypoxia as well as free heme (184; reviewed in 178).”
- Targeting cellular metabolism to improve cancer therapeutics (2013, background): “Active drug efflux is also fueled by glycolytic ATP production and HIF-1a-induced transporter overexpression resulting in a significant decrease in the cytoplasmic retention of many anticancer agents.(110,111) HIF-1a overexpression also induces cellular compensations that can bypass the mechanisms o”
- ABC multidrug transporters: structure, function and role in chemoresistance. (2008, background): “In stem cells, ABCG2 appears to interact with heme and prevent accumulation of porphyrins, enhancing cell survival under hypoxic conditions [18].”
- Mechanisms and insights into drug resistance in cancer (2013, background): “…Park and Gerson, 2005), changes in cell cycle parameters (Venezia et al., 2004), overexpression of anti-apoptotic proteins (Wang et al., 2003) or drug transporters (Gottesman et al., 2002; Krishnamurthy et al., 2004), etc., resistance of CSCs could be due to their quiescent nature (Teicher, 2006).”
- Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy (2012, background): “First, HIFs have been shown to regulate the expression of genes encoding ATP-binding cassette multidrug transporters, including MDR1 (ABCB1) and BCRP (ABCG2), which efflux chemotherapy drugs from cancer cells [77, 78].”
- Metabolic regulation of hematopoietic stem cells in the hypoxic niche. (2011, background): “Hypoxia also maintains the SP phenotype in HSC cultures (Krishnamurthy et al., 2004).”
- Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation (2010, background): “Because of the ability of BCRP to transport porphyrins and heme, the role of Bcrp in protecting against hypoxic injury has been investigated in Bcrp-null mice (Krishnamurthy et al., 2004).”