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Zinc supplementation augments in vivo antitumor effect of chemotherapy by restoring p53 function
Author(s) -
Margalit Ofer,
Simon Amos J.,
Yakubov Eduard,
Puca Rosa,
Yosepovich Ady,
Avivi Camila,
JacobHirsch Jasmine,
Gelernter Ilana,
Harmelin Alon,
Barshack Iris,
Rechavi Gideon,
D'Orazi Gabriella,
Givol David,
Amariglio Ninette
Publication year - 2011
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.26441
Subject(s) - cancer research , in vivo , mammary tumor , biology , transcription factor , suppressor , tumor suppressor gene , cancer , medicine , breast cancer , carcinogenesis , gene , biochemistry , microbiology and biotechnology
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.