title: Zinc protoporphyrin suppresses cancer cell viability through a heme oxygenase-1-independent mechanism: the involvement of the Wnt/β-catenin signaling pathway.
abstract: Zinc protoporphyrin (ZnPP), a known inhibitor of heme oxygenase-1 (HO-1), has been reported to have anticancer activity in both in vitro and in vivo model systems. While the mechanisms of ZnPP's anticancer activity remain to be elucidated, it is generally believed that ZnPP suppresses tumor growth through inhibition of HO-1 activity. We examined this hypothesis by altering cellular levels of HO-1 in human ovarian (A2780) and prostate cancer (DU145) cells and found that ZnPP inhibits cancer cell viability through an HO-1-independent mechanism. Neither over-expression nor knockdown of HO-1 significantly alters ZnPP's cytotoxicity in human cancer cells, indicating that HO-1 does not mediate ZnPP's inhibitory effect on cancer cell growth. Consistent with these observations, tin protoporphyrin (SnPP), a well-established HO-1 inhibitor, was found to be much less cytotoxic than ZnPP, and docosahexaenoic acid (DHA), an HO-1 inducer, enhanced ZnPP's cytotoxicity. In an effort to define the mechanisms of ZnPP-induced cytotoxicity, we found that ZnPP but not SnPP, diminished β-catenin expression through proteasome degradation and potently suppressed β-catenin-mediated signaling in our model systems. Thus, ZnPP-induced cytotoxicity is independent of HO-1 expression in cancer cells and the Wnt/β-catenin pathway is potentially involved in ZnPP's anticancer activity.
authors.affiliation: Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: Shuai
authors.initials: S
authors.lastname: Wang
authors.forename: Jori E
authors.initials: JE
authors.lastname: Avery
authors.forename: Bethany N
authors.initials: BN
authors.lastname: Hannafon
authors.forename: Stuart E
authors.initials: SE
authors.lastname: Lind
authors.forename: Wei-Qun
authors.initials: WQ
authors.lastname: Ding
mesh_terms: D001483:Base Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D017931:DNA Primers; D005260:Female; D017930:Genes, Reporter; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008856:Microscopy, Fluorescence; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D011524:Protoporphyrins / Q000494:pharmacology*; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D011524:Protoporphyrins; D034741:RNA, Small Interfering; D051153:Wnt Proteins; D051176:beta Catenin; C017803:zinc protoporphyrin; D051547:Heme Oxygenase-1