ironjustice
2013-03-14 14:54:30 UTC
Modulation of intracellular iron metabolism by iron chelation affects
chromatin remodeling proteins and corresponding epigenetic
modifications in breast cancer cells and increases their sensitivity
to chemotherapeutic agents.
Pogribny IP, Tryndyak VP, Pogribna M, Shpyleva S, Surratt G, Gamboa da
Costa G, Beland FA.
Int J Oncol. 2013 Mar 12.
Division of Biochemical Toxicology, National Center for Toxicological
Research, FDA, Jefferson, AR 72079, USA.
Abstract
Iron plays a vital role in the normal functioning of cells via the
regulation of essential cellular metabolic reactions, including
several DNA and histone-modifying proteins.
The metabolic status of iron and the regulation of epige-netic
mechanisms are well-balanced and tightly controlled in normal cells;
however, in cancer cells these processes are profoundly disturbed.
Cancer-related abnormalities in iron metabolism have been corrected
through the use of iron-chelating agents, which cause an inhibition of
DNA synthesis, G1-S phase arrest, an inhibition of epithelial-to-
mesenchymal transition, and the activation of apoptosis.
In the present study, we show that, in addition to these well-studied
molecular mechanisms, the treatment of wild-type TP53 MCF-7 and mutant
TP53 MDA-MB-231 human breast cancer cells with desferrioxamine (DFO),
a model iron chelator, causes significant epigenetic alterations at
the global and gene-specific levels.
Specifically, DFO treatment decreased the protein levels of the
histone H3 lysine 9 demethylase, Jumonji domain-containing protein 2A
(JMJD2A), in the MCF-7 and MDA-MB-231 cells and down-regulated the
levels of the histone H3 lysine 4 demethylase, lysine-specific
demethylase 1 (LSD1), in the MDA-MB-231 cells. These changes were
accompanied by alterations in corresponding metabolically sensitive
histone marks.
Additionally, we demonstrate that DFO treatment activates apoptotic
programs in MCF-7 and MDA-MB-231 cancer cells and enhances their
sensitivity to the chemotherapeutic agents, doxorubicin and cisplatin;
however, the mechanisms underlying this activation differ.
The induction of apoptosis in wild-type TP53 MCF-7 cells was p53-
dependent, triggered mainly by the down-regulation of the JMJD2A
histone demethylase, while in mutant TP53 MDA-MB-231 cells, the
activation of the p53-independent apoptotic program was driven
predominantly by the epigenetic up-regulation of p21.
PMID:23483119
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Tom
Jesus Was A Vegetarian!
http://tinyurl.com/2r2nkh
Man Is A Herbivore!
http://tinyurl.com/4rq595
DEAD PEOPLE WALKING
http://tinyurl.com/zk9fk
chromatin remodeling proteins and corresponding epigenetic
modifications in breast cancer cells and increases their sensitivity
to chemotherapeutic agents.
Pogribny IP, Tryndyak VP, Pogribna M, Shpyleva S, Surratt G, Gamboa da
Costa G, Beland FA.
Int J Oncol. 2013 Mar 12.
Division of Biochemical Toxicology, National Center for Toxicological
Research, FDA, Jefferson, AR 72079, USA.
Abstract
Iron plays a vital role in the normal functioning of cells via the
regulation of essential cellular metabolic reactions, including
several DNA and histone-modifying proteins.
The metabolic status of iron and the regulation of epige-netic
mechanisms are well-balanced and tightly controlled in normal cells;
however, in cancer cells these processes are profoundly disturbed.
Cancer-related abnormalities in iron metabolism have been corrected
through the use of iron-chelating agents, which cause an inhibition of
DNA synthesis, G1-S phase arrest, an inhibition of epithelial-to-
mesenchymal transition, and the activation of apoptosis.
In the present study, we show that, in addition to these well-studied
molecular mechanisms, the treatment of wild-type TP53 MCF-7 and mutant
TP53 MDA-MB-231 human breast cancer cells with desferrioxamine (DFO),
a model iron chelator, causes significant epigenetic alterations at
the global and gene-specific levels.
Specifically, DFO treatment decreased the protein levels of the
histone H3 lysine 9 demethylase, Jumonji domain-containing protein 2A
(JMJD2A), in the MCF-7 and MDA-MB-231 cells and down-regulated the
levels of the histone H3 lysine 4 demethylase, lysine-specific
demethylase 1 (LSD1), in the MDA-MB-231 cells. These changes were
accompanied by alterations in corresponding metabolically sensitive
histone marks.
Additionally, we demonstrate that DFO treatment activates apoptotic
programs in MCF-7 and MDA-MB-231 cancer cells and enhances their
sensitivity to the chemotherapeutic agents, doxorubicin and cisplatin;
however, the mechanisms underlying this activation differ.
The induction of apoptosis in wild-type TP53 MCF-7 cells was p53-
dependent, triggered mainly by the down-regulation of the JMJD2A
histone demethylase, while in mutant TP53 MDA-MB-231 cells, the
activation of the p53-independent apoptotic program was driven
predominantly by the epigenetic up-regulation of p21.
PMID:23483119
Who loves ya.
Tom
Jesus Was A Vegetarian!
http://tinyurl.com/2r2nkh
Man Is A Herbivore!
http://tinyurl.com/4rq595
DEAD PEOPLE WALKING
http://tinyurl.com/zk9fk