Suppression of PI3K/mTOR pathway rescues LLC cells from cell death induced by hypoxia.
Suppression of PI3K/mTOR pathway rescues LLC cells from cell death induced by hypoxia.
复制标题
DOI：
10.1016/j.bbrc.2005.02.163
复制
发表时间：
2005-04
影响因子：
3.1
通讯作者：
Y. Hamanaka;M. Mukai;M. Shimamura;T. Kitagawa;T. Nishida;F. Isohashi;T. Ito;Y. Nishizawa;M. Tatsuta;H. Matsuda;M. Inoue
中科院分区：
文献类型：
--
作者：
Y. Hamanaka;M. Mukai;M. Shimamura;T. Kitagawa;T. Nishida;F. Isohashi;T. Ito;Y. Nishizawa;M. Tatsuta;H. Matsuda;M. Inoue
实体瘤中的癌细胞受到包括缺氧在内的各种微环境应激的挑战，并且缺氧区域中的癌细胞对当前的癌症疗法具有抗性。为了研究癌细胞耐缺氧的机制，我们检测了小鼠刘易斯肺癌（LLC）细胞，该细胞在缺氧条件下由于高密度坏死而死亡，而在常氧条件下则没有。据报道，哺乳动物雷帕霉素靶蛋白（mTOR）（细胞能量的中心调节因子）的水平在缺氧中受到抑制。我们发现，磷酸化的两个分子下游，核糖体p70 S6激酶（S6K）和核糖体蛋白S6，显着抑制缺氧。过表达活性形式的S6K增加了LLC细胞对缺氧的敏感性。另一方面，在缺氧条件下，抑制PI3K或mTOR显著减少缺氧诱导的细胞死亡。在缺氧条件下，阻断PI3K或mTOR通路增加细胞内ATP水平，并延迟培养基中pH和葡萄糖水平的降低，而不影响细胞周期。
Cancer cells in solid tumors are challenged by various microenvironmental stresses, including hypoxia, and cancer cells in hypoxic regions are resistant to current cancer therapies. To investigate the mechanism of resistance to hypoxia in cancer cells, we examined mouse Lewis lung carcinoma (LLC) cells, which died due to necrosis at high density under hypoxic but not under normoxic conditions. Levels of mammalian target of rapamycin (mTOR), a central regulator of cellular energy, are reported to be suppressed in hypoxia. We found that phosphorylation of two molecules downstream to it, ribosomal p70 S6 kinase (S6K) and ribosomal protein S6, was markedly suppressed by hypoxia. Overexpression of the active form of S6K increased the sensitivity of LLC cells to hypoxia. On the other hand, inhibition of PI3K or mTOR dramatically reduced hypoxia-induced cell death under hypoxic conditions. Under hypoxic conditions, blockade of the PI3K or mTOR pathway increased levels of intracellular ATP and delayed decreases in pH and glucose level in culture medium, without affecting the cell cycle.