Chloramphenicol causes mitochondrial stress, decreases ATP biosynthesis, induces matrix metalloproteinase-13 expression, and solid-tumor cell invasion.
Chloramphenicol causes mitochondrial stress, decreases ATP biosynthesis, induces matrix metalloproteinase-13 expression, and solid-tumor cell invasion.
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DOI：
10.1093/toxsci/kfq085
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发表时间：
2010-07
期刊：
影响因子：
--
通讯作者：
Kang JJ
中科院分区：
文献类型：
--
作者：
Li CH;Cheng YW;Liao PL;Yang YT;Kang JJ
过度使用和滥用抗生素会增加患癌症的风险。氯霉素可以抑制细菌和线粒体蛋白的合成，引起线粒体应激，减少ATP的生物合成。氯霉素可以加速癌症的发展；然而，氯霉素在癌变和癌症进展中的潜在机制尚不清楚。我们发现氯霉素在条件培养基中诱导基质金属蛋白酶（matrix metalloproteinase， MMP）-13的表达，增加MMP-13蛋白，导致癌细胞侵袭增加。氯霉素还激活c-Jun n末端激酶（JNK）和磷脂酰肌醇3-激酶(PI-3K)/Akt信号通路，导致c-Jun蛋白磷酸化。活化的c-Jun蛋白已被证明可以激活与MMP-13启动子的结合，并上调MMP-13的数量。SP 600125 （JNK抑制剂）和LY 294002 （PI-3K/Akt抑制剂）均能抑制氯霉素诱导的c-Jun磷酸化、MMP-13表达和细胞侵袭。JNK和PI-3K p85亚基的过表达也能抑制氯霉素诱导的反应。其他引起线粒体应激和ATP生物合成减少的抗生素也会诱导MMP-13的表达。这些发现表明，氯霉素诱导的PI-3K/Akt、JNK磷酸化和激活蛋白1激活可能作为一种新的线粒体应激信号，导致MMP-13表达增加和MMP-13相关的癌细胞侵袭。本研究结果证实，氯霉素和其他70S核糖体抑制剂应谨慎使用，特别是在癌症治疗期间。
Overuse and abuse of antibiotics can increase the risk of cancer. Chloramphenicol can inhibit both bacterial and mitochondrial protein synthesis, causing mitochondrial stress and decreased ATP biosynthesis. Chloramphenicol can accelerate cancer progression; however, the underlying mechanisms of chloramphenicol in carcinogenesis and cancer progression are still unclear. We found that chloramphenicol can induce matrix metalloproteinase (MMP)-13 expression and increase MMP-13 protein in conditioned medium, resulting in an increase in cancer cell invasion. Chloramphenicol also activated c-Jun N-terminal kinases (JNK) and phosphatidylinositol 3-kinase (PI-3K)/Akt signaling, leading to c-Jun protein phosphorylation. The activated c-Jun protein has been proven to activate binding to the MMP-13 promoter and also upregulate the amount of MMP-13. Both the SP 600125 (JNK inhibitor) and LY 294002 (PI-3K/Akt inhibitor) can inhibit chloramphenicol-induced c-Jun phosphorylation, MMP-13 expression, and cell invasion. Overexpression of the dominant-negative JNK and PI-3K p85 subunit also negate chloramphenicol-induced responses. Other antibiotics that cause mitochondrial stress and a decrease in ATP biosynthesis also induce MMP-13 expression. These findings suggest that chloramphenicol-induced PI-3K/Akt, JNK phosphorylation, and activator protein 1 activation might function as a novel mitochondrial stress signal that result in an increase of MMP-13 expression and MMP-13-associated cancer cell invasion. The findings of this study confirms that chloramphenicol, and other 70S ribosomal inhibitors, should be administered with caution, especially during cancer therapy.
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DOI：
10.1046/j.1432-1327.1998.2530067.x
发表时间：
1998-04-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Nakamura, H;Fujii, Y;Okada, Y
通讯作者：
Okada, Y
影响因子：
4.8
作者：
Leivonen, SK;Chantry, A;Kähäri, VM
通讯作者：
Kähäri, VM
DOI：
10.1124/jpet.102.048611
发表时间：
2003-06-01
影响因子：
3.5
作者：
Ahmed, S;Rahman, A;Haqqi, TM
通讯作者：
Haqqi, TM
影响因子：
2.7
作者：
Hamer, Isabelle;Delaive, Edouard;Arnould, Thierry
通讯作者：
Arnould, Thierry
影响因子：
4.8
作者：
Holtkamp, Nikola;Atallah, Isis;von Deimling, Andreas
通讯作者：
von Deimling, Andreas