Protein kinase C-ERK1/2 signal pathway switches glucose depletion-induced necrosis to apoptosis by regulating superoxide dismutases and suppressing reactive oxygen species production in A549 lung cancer cells
Protein kinase C-ERK1/2 signal pathway switches glucose depletion-induced necrosis to apoptosis by regulating superoxide dismutases and suppressing reactive oxygen species production in A549 lung cancer cells
复制标题
DOI：
10.1002/jcp.20941
复制
发表时间：
2007-05-01
影响因子：
5.6
通讯作者：
Kang, Ho Sung
中科院分区：
文献类型：
--
作者：
Kim, Cho Hee;Han, Song Iy;Kang, Ho Sung
细胞通常不是死于凋亡就是死于坏死。然而，对于整个生物体来说，细胞凋亡和坏死的后果是完全不同的。在细胞凋亡的情况下，细胞内容物仍然堆积在被巨噬细胞去除的凋亡小体中，因此不会发生炎症；在坏死期间，细胞膜破裂，胞液成分释放到细胞外空间引发炎症。最近，炎症和坏死被认为是促进肿瘤生长的因素。我们研究了葡萄糖耗竭(GD)引起细胞死亡的分子机制，这是肿瘤微环境的一个共同特征。Gd通过产生活性氧(ROS)诱导A549肺癌细胞坏死。N-乙酰-L-半胱氨酸和过氧化氢酶抑制ROS的产生，阻止了细胞的坏死，并将依赖于caspase-9和caspase-3激活的线粒体死亡途径的细胞死亡模式转变为凋亡，表明ROS在确定GD诱导的细胞死亡模式中起着关键作用。我们证明，依赖蛋白激酶C的细胞外调节激酶1/2(ERK 1/2)的激活也通过抑制ROS的产生而将GD诱导的坏死转化为细胞凋亡，这可能是通过诱导锰超氧化物歧化酶(SOD)的表达和阻止GD诱导的铜锌SOD的降解来实现的。因此，这些结果表明，包括GD的细胞死亡模式是由调节MnSOD和CuZnSOD的蛋白激酶C/ERK1/2信号通路决定的，这些抗氧化剂可能通过诱导从坏死到凋亡的开关来发挥其已知的肿瘤抑制活性。
Cells typically die by either apoptosis or necrosis. However, the consequences of apoptosis and necrosis are quite different for a whole organism. In the case of apoptosis, the cell content remains packed in the apoptotic bodies that are removed by marcrophages, and thereby inflammation does not occur; during necrosis, the cell membrane is ruptured, and the cytosolic constituents are released into the extracellular space provoking inflammation. Recently, inflammation and necrosis have been suggested to promote tumor growth. We investigated the molecular mechanism underlying cell death in response to glucose depletion (GD), a common characteristic of the tumor microenvironment. GD induced necrosis through production of reactive oxygen species (ROS) in A549 lung carcinoma cells. Inhibition of ROS production by N-acetyl-L-cysteine and catalase prevented necrosis and switched the cell death mode to apoptosis that depends on mitochondrial death pathway involving caspase-9 and caspase-3 activation, indicating a critical role of ROS in determination of GD-induced cell death mode. We demonstrate that protein kinase C-dependent extracellular regulated kinase 1/2 (ERK 1/2) activation also switched GD-induced necrosis to apoptosis through inhibition of ROS production possibly by inducing manganese superoxide dismutase (SOD) expression and by preventing GD-induced degradation of cupper zinc SOD. Thus, these results suggest that GD-incluced cell death mode is determined by the protein kinase C/ERK 1/2 signal pathway that regulates MnSOD and CuZnSOD and that these antioxidants may exert their known tumor suppressive activities by inducing necrosis-to-apoptosis switch.