The stem cell marker Bcrp/ABCG2 enhances hypoxic cell survival through interactions with heme.
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.
Krishnamurthy
Partha
P
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-2794, USA.
Ross
Douglas D
DD
Nakanishi
Takeo
T
Bailey-Dell
Kim
K
Zhou
Sheng
S
Mercer
Kelly E
KE
Sarkadi
Balazs
B
Sorrentino
Brian P
BP
Schuetz
John D
JD
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
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