p53 Regulates oxidative stress-mediated retrograde signaling: a novel mechanism for chemotherapy-induced cardiac injury.
p53 Regulates oxidative stress-mediated retrograde signaling: a novel mechanism for chemotherapy-induced cardiac injury.
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DOI：
10.1371/journal.pone.0018005
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发表时间：
2011-03-30
期刊：
影响因子：
3.7
通讯作者：
St Clair DK
中科院分区：
文献类型：
--
作者：
Velez JM;Miriyala S;Nithipongvanitch R;Noel T;Plabplueng CD;Oberley T;Jungsuwadee P;Van Remmen H;Vore M;St Clair DK
癌症治疗对正常组织的副作用限制了治疗的成功。活性氧物质（ROS）的产生涉及许多化疗剂，包括多柔比星（DOX），一种有效的癌症化疗药物。DOX产生的ROS与DNA损伤、p53核转位和线粒体损伤有关;然而，这些事件背后的因果关系和分子机制尚不清楚。本研究使用野生型（WT）和p53纯合敲除（p53−/−）小鼠来研究p53在线粒体和细胞核之间的串扰中的作用。通过对4-羟基-2 ′-壬烯醛（4 HNE）-加合蛋白（一种与蛋白质结合的脂质过氧化产物）水平的免疫金分析，证明向小鼠注射DOX（20 mg/kg）可引起心脏组织中的氧化应激。WT DOX处理的小鼠的细胞核和线粒体中的4 HNE水平增加，但仅在DOX处理的p53（-/-）小鼠的细胞核中增加，这暗示p53在引起DOX诱导的线粒体氧化应激中起关键作用。应激活化蛋白c-Jun氨基末端激酶（JNK）在WT小鼠中响应于增加的4 HNE而被激活，但在接受DOX治疗的p53（−/−）小鼠中没有，如通过HNE和pJNK的免疫共沉淀所确定的。DOX处理的WT小鼠中JNK的活化伴随着Bcl-2从线粒体中的Beclin解离和诱导II型细胞死亡（自噬性细胞死亡），如通过LC 3-I/LC-3-II比率和γ-H2 AX（DNA损伤的生物标志物）的增加所证明的。通过定量形态学评估，p53的缺失显著降低了线粒体损伤，通过左心室射血分数和缩短分数评估，显著降低了心功能下降。这些结果表明，p53在DOX诱导的心脏毒性中起关键作用，部分是通过诱导氧化应激介导的逆行信号传导。
The side effects of cancer therapy on normal tissues limit the success of therapy. Generation of reactive oxygen species (ROS) has been implicated for numerous chemotherapeutic agents including doxorubicin (DOX), a potent cancer chemotherapeutic drug. The production of ROS by DOX has been linked to DNA damage, nuclear translocation of p53, and mitochondrial injury; however, the causal relationship and molecular mechanisms underlying these events are unknown. The present study used wild-type (WT) and p53 homozygous knock-out (p53−/−) mice to investigate the role of p53 in the crosstalk between mitochondria and nucleus. Injecting mice with DOX (20 mg/kg) causes oxidative stress in cardiac tissue as demonstrated by immunogold analysis of the levels of 4-hydroxy-2′-nonenal (4HNE)-adducted protein, a lipid peroxidation product bound to proteins. 4HNE levels increased in both nuclei and mitochondria of WT DOX-treated mice but only in nuclei of DOX-treated p53(−/−) mice, implicating a critical role for p53 in causing DOX-induced oxidative stress in mitochondria. The stress-activated protein c-Jun amino-terminal kinase (JNKs) was activated in response to increased 4HNE in WT mice but not p53(−/−) mice receiving DOX treatment, as determined by co-immunoprecipitation of HNE and pJNK. The activation of JNK in DOX treated WT mice was accompanied by Bcl-2 dissociation from Beclin in mitochondria and induction of type II cell death (autophagic cell death), as evidenced by an increase in LC3-I/LC-3-II ratio and γ-H2AX, a biomarker for DNA damage. The absence of p53 significantly reduces mitochondrial injury, assessed by quantitative morphology, and decline in cardiac function, assessed by left ventricular ejection fraction and fraction shortening. These results demonstrate that p53 plays a critical role in DOX-induced cardiac toxicity, in part, by the induction of oxidative stress mediated retrograde signaling.
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DOI：
10.1253/circj.cj-08-0669
发表时间：
2008-01-01
期刊：
Circulation journal : official journal of the Japanese Circulation Society
影响因子：
--
作者：
Nishida, Kazuhiko;Otsu, Kinya
通讯作者：
Otsu, Kinya
DOI：
10.1002/tera.1420070306
发表时间：
1973-01-01
期刊：
TERATOLOGY
影响因子：
--
作者：
SCHWEICHEL, JU;MERKER, HJ
通讯作者：
MERKER, HJ
影响因子：
4.8
作者：
Bulteau, AL;Lundberg, KC;Szweda, LI
通讯作者：
Szweda, LI
影响因子：
5.7
作者：
Chaiswing, L;Cole, MP;Oberley, TD
通讯作者：
Oberley, TD
影响因子：
4.3
作者：
Shizukuda, Y;Matoba, S;Hwang, PM
通讯作者：
Hwang, PM