Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Korea.
Oncogene. 2010 Jan 28;29(4):561-75. doi: 10.1038/onc.2009.355. Epub 2009 Oct 26.
Premature senescence is considered as a cellular defense mechanism to prevent tumorigenesis. Although recent evidences show that c-Jun N-terminal kinase (JNK) is involved in the senescence process, the mechanism for this regulation is not fully understood. Here, we examined the role of JNK in premature senescence of tumor cells. Treatment of cells with the JNK-specific inhibitor SP600125 caused phenotypical changes of senescence and triggered a rapid increase in mitochondrial reactive oxygen species (ROS) production and DNA-damage response (DDR) in MCF7 breast carcinoma cells. ROS generation was attributed to the suppression of B-cell lymphoma-2 (Bcl-2) phosphorylation, and resulted in DNA damage and p53 activation. Bax did not change their localization to the mitochondria, which is required for apoptosis. The essential roles of JNK and phosphorylated Bcl-2 in preventing premature senescence were confirmed using RNA interference and ectopic expression of mutants of Bcl-2, including phosphomimetic and nonphosphorylatable forms. These findings were evidenced in H460 lung carcinoma cells and primary human embryonic fibroblasts. Altogether, our results showed that loss of JNK activity triggers a Bcl-2/ROS/DDR signaling cascade that ultimately leads to premature senescence, indicating that basal JNK activity is essential in preventing premature senescence.
过早衰老被认为是一种防止肿瘤发生的细胞防御机制。尽管最近的证据表明 c-Jun N 末端激酶（JNK）参与了衰老过程，但这种调节的机制尚不完全清楚。在这里，我们研究了 JNK 在肿瘤细胞过早衰老中的作用。用 JNK 特异性抑制剂 SP600125 处理细胞会引起衰老的表型变化，并在 MCF7 乳腺癌细胞中迅速引发线粒体活性氧（ROS）产生和 DNA 损伤反应（DDR）的增加。ROS 的产生归因于 B 细胞淋巴瘤-2（Bcl-2）磷酸化的抑制，导致 DNA 损伤和 p53 激活。Bax 没有改变其向线粒体的定位，这是凋亡所必需的。使用 RNA 干扰和 Bcl-2 的突变体（包括磷酸模拟和不可磷酸化形式）的异位表达，证实了 JNK 和磷酸化 Bcl-2 在防止过早衰老中的重要作用。这些发现在 H460 肺癌细胞和原代人胚胎成纤维细胞中得到了证实。总之，我们的研究结果表明，JNK 活性的丧失会触发 Bcl-2/ROS/DDR 信号级联反应，最终导致过早衰老，表明基础 JNK 活性对于防止过早衰老至关重要。
