title: Zinc supplementation augments in vivo antitumor effect of chemotherapy by restoring p53 function.
abstract: Activated p53 is necessary for tumor suppression. Homeodomain-interacting protein kinase-2 (HIPK2) is a positive regulator of functional p53. HIPK2 modulates wild-type p53 activity toward proapoptotic transcription and tumor suppression by the phosphorylation of serine 46. Knock-down of HIPK2 interferes with tumor suppression and sensitivity to chemotherapy. Combined administration of adriamycin and zinc restores activity of misfolded p53 and enables the induction of its proapoptotic and tumor suppressor functions in vitro and in vivo. We therefore looked for a cancer model where HIPK2 expression is low. MMTV-neu transgenic mice overexpressing HER2/neu, develop mammary tumors at puberty with a long latency, showing very low expression of HIPK2. Here we show that whereas these tumors are resistant to adriamycin treatment, a combination of adriamycin and zinc suppresses tumor growth in vivo in these mice, an effect evidenced by the histological features of the mammary tumors. The combined treatment of adriamycin and zinc also restores wild-type p53 conformation and induces proapoptotic transcription activity. These findings may open up new possibilities for the treatment of human cancers via the combination of zinc with chemotherapeutic agents, for a selected group of patients expressing low levels of HIPK2, with an intact p53. In addition, HIPK2 may serve as a new biomarker for tumor aggressiveness.
authors.affiliation: Cancer Research Center, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Ofer
authors.initials: O
authors.lastname: Margalit
authors.forename: Amos J
authors.initials: AJ
authors.lastname: Simon
authors.forename: Eduard
authors.initials: E
authors.lastname: Yakubov
authors.forename: Rosa
authors.initials: R
authors.lastname: Puca
authors.forename: Ady
authors.initials: A
authors.lastname: Yosepovich
authors.forename: Camila
authors.initials: C
authors.lastname: Avivi
authors.forename: Jasmine
authors.initials: J
authors.lastname: Jacob-Hirsch
authors.forename: Ilana
authors.initials: I
authors.lastname: Gelernter
authors.forename: Alon
authors.initials: A
authors.lastname: Harmelin
authors.forename: Iris
authors.initials: I
authors.lastname: Barshack
authors.forename: Gideon
authors.initials: G
authors.lastname: Rechavi
authors.forename: Gabriella
authors.initials: G
authors.lastname: D'Orazi
authors.forename: David
authors.initials: D
authors.lastname: Givol
authors.forename: Ninette
authors.initials: N
authors.lastname: Amariglio
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D001483:Base Sequence; D017931:DNA Primers; D004317:Doxorubicin / Q000627:therapeutic use*; D018734:Genes, erbB-2; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000821:virology; D008324:Mammary Tumor Virus, Mouse / Q000302:isolation & purification; D051379:Mice; D008822:Mice, Transgenic; D017510:Protein Folding; D060888:Real-Time Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology*; D015032:Zinc / Q000008:administration & dosage*
chemical_list: D000970:Antineoplastic Agents; D017931:DNA Primers; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D015032:Zinc