title: The stem cell marker Bcrp/ABCG2 enhances hypoxic cell survival through interactions with heme.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-2794, USA.
authors.forename: Partha
authors.initials: P
authors.lastname: Krishnamurthy
authors.forename: Douglas D
authors.initials: DD
authors.lastname: Ross
authors.forename: Takeo
authors.initials: T
authors.lastname: Nakanishi
authors.forename: Kim
authors.initials: K
authors.lastname: Bailey-Dell
authors.forename: Sheng
authors.initials: S
authors.lastname: Zhou
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Mercer
authors.forename: Balazs
authors.initials: B
authors.lastname: Sarkadi
authors.forename: Brian P
authors.initials: BP
authors.lastname: Sorrentino
authors.forename: John D
authors.initials: JD
authors.lastname: Schuetz
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D001692:Biological Transport; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000378:metabolism; D002470:Cell Survival; D004396:Coloring Agents / Q000494:pharmacology; D004970:Estrone / Q000031:analogs & derivatives* / Q000737:chemistry; D006418:Heme / Q000737:chemistry*; D006427:Hemin / Q000737:chemistry; D006801:Humans; D000860:Hypoxia; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009154:Mutation; D041681:NIH 3T3 Cells; D009363:Neoplasm Proteins / Q000378:metabolism / Q000502:physiology*; D010100:Oxygen / Q000378:metabolism; D011166:Porphyrins / Q000737:chemistry; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011524:Protoporphyrins / Q000737:chemistry; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012685:Sepharose / Q000494:pharmacology; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D015533:Transcriptional Activation; D019076:Transgenes; D015854:Up-Regulation
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D004396:Coloring Agents; D009363:Neoplasm Proteins; D011166:Porphyrins; D011524:Protoporphyrins; D004970:Estrone; D006418:Heme; D006427:Hemin; D012685:Sepharose; C028025:protoporphyrin IX; C017296:estrone sulfate; D010100:Oxygen