Zinc Protoporphyrin Regulates Cyclin D1 Expression Independent of Heme Oxygenase Inhibition

Division of Neonatology, Children's Hospital of Philadelphia, PA 19104, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 10/2009; 284(52):36302-11. DOI: 10.1074/jbc.M109.031641
Source: PubMed


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.

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    • "While induction of HO-1 in normal cells is cytoprotective and antiinflammatory [73,74], expression of HO-1 in cancer cells may support malignant growth [75] and render cancer cells more resistant to chemotherapy [21]. In fact, HO-1 has been proposed as a potential cellular target for cancer therapy [22], and HO-1 inhibitors such as zinc protoporphyrin have been reported to suppress cancer growth in vitro and in vivo [76] [77] [78]. Therefore, the combination of DHA and HO- 1 inhibitors could be an attractive approach to more effectively suppress cancer growth, and future work to investigate this potential combinatorial approach is justified. "
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