Zinc protoporphyrin regulates cyclin D1 expression independent of heme oxygenase inhibition.
Zinc protoporphyrin IX (ZnPP), an endogenous heme analogue that inhibits heme oxygenase (HO) activity, represses tumor growth. It can also translocate into the nucleus and up-regulate heme oxygenase 1 (HMOX1) gene expression. Here, we demonstrate that tumor cell proliferation was inhibited by ZnPP, whereas tin protoporphyrin (SnPP), another equally potent HO-1 inhibitor, had no effect. Microarray analysis on 128 tumorigenesis related genes showed that ZnPP suppressed genes involved in cell proliferation and angiogenesis. Among these genes, CYCLIN D1 (CCND1) was specifically inhibited as were its mRNA and protein levels. Additionally, ZnPP inhibited CCND1 promoter activity through an Sp1 and Egr1 overlapping binding site (S/E). We confirmed that ZnPP modulated the S/E site, at least partially by associating with Sp1 and Egr1 proteins rather than direct binding to DNA targets. Furthermore, administration of ZnPP significantly inhibited cyclin D1 expression and progression of a B-cell leukemia/lymphoma 1 tumor in mice by preferentially targeting tumor cells. These observations show HO independent effects of ZnPP on cyclin D1 expression and tumorigenesis.
La
Ping
P
Division of Neonatology, Children's Hospital of Philadelphia, Pennsylvania 19104.
Fernando
Amal P
AP
Division of Neonatology, Children's Hospital of Philadelphia, Pennsylvania 19104.
Wang
Zhi
Z
Division of Neonatology, Children's Hospital of Philadelphia, Pennsylvania 19104.
Salahudeen
Ameen
A
Division of Neonatology, Children's Hospital of Philadelphia, Pennsylvania 19104.
Yang
Guang
G
Division of Neonatology, Children's Hospital of Philadelphia, Pennsylvania 19104.
Lin
Qing
Q
Division of Neonatology, Children's Hospital of Philadelphia, Pennsylvania 19104; Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104.
Wright
Clyde J
CJ
Division of Neonatology, Children's Hospital of Philadelphia, Pennsylvania 19104.
Dennery
Phyllis A
PA
Division of Neonatology, Children's Hospital of Philadelphia, Pennsylvania 19104; Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104. Electronic address: dennery@email.chop.edu.
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism*; D051766:Early Growth Response Protein 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D056945:Hep G2 Cells; D006801:Humans; D020014:K562 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000201:enzymology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000201:enzymology; D020411:Oligonucleotide Array Sequence Analysis; D011524:Protoporphyrins / Q000494:pharmacology*; D020218:Response Elements; D016329:Sp1 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism
C530104:CCND1 protein, human; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D004791:Enzyme Inhibitors; D011524:Protoporphyrins; D016329:Sp1 Transcription Factor; D019938:Cyclin D1; C017803:zinc protoporphyrin; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1