Research Institute, National Cancer Center, Ilsan-gu, Goyang-si, Gyeonggi-do 410-769, Korea.
Int J Mol Sci. 2013 Aug 22;14(9):17304-18. doi: 10.3390/ijms140917304.
The present study identified a novel salinomycin (Sal)-sensitization mechanism in cancer cells. We analyzed the signal proteins Akt, Jnk, p38, Jak, and Erk1/2 in cancer cell lines that had arrested growth following low amounts of Sal treatment. We also tested the signal molecules PI3K, PDK1, GSK3β, p70S6K, mTOR, and PTEN to analyze the PI3K/Akt/mTOR pathway. The results showed that Sal sensitization positively correlates with large reductions in p70S6K activation. Interestingly, Akt was the only signal protein to be significantly activated by Sal treatment. The Akt activation appeared to require the PI3K pathway as its activation was abolished by the PI3K inhibitors LY294002 and wortmannin. The Akt activation by Sal was conserved in the other cell lines analyzed, which originated from other organs. Both Akt activation and C-PARP production were proportionally increased with increased doses of Sal. In addition, the increased levels of pAkt were not reduced over the time course of the experiment. Co-treatment with Akt inhibitors sensitized the Sal-treated cancer cells. The results thereby suggest that Akt activation is increased in cells that survive Sal treatment and resist the cytotoxic effect of Sal. Taken together; these results indicate that Akt activation may promote the resistance of cancer cells to Sal.
本研究确定了一种新型盐霉素（Sal）在癌细胞中的增敏机制。我们分析了在低剂量 Sal 处理后生长停滞的癌细胞系中的信号蛋白 Akt、Jnk、p38、Jak 和 Erk1/2。我们还测试了信号分子 PI3K、PDK1、GSK3β、p70S6K、mTOR 和 PTEN，以分析 PI3K/Akt/mTOR 通路。结果表明，Sal 增敏与 p70S6K 激活的大幅减少呈正相关。有趣的是，Akt 是唯一被 Sal 处理显著激活的信号蛋白。Akt 的激活似乎需要 PI3K 途径，因为其激活被 PI3K 抑制剂 LY294002 和 wortmannin 所阻断。在其他来源的不同器官的细胞系中，Sal 对 Akt 的激活是保守的。随着 Sal 剂量的增加，Akt 的激活和 C-PARP 的产生都呈比例增加。此外，在实验过程中，增加的 pAkt 水平没有减少。用 Akt 抑制剂共同处理可使 Sal 处理的癌细胞敏感。结果表明，在 Sal 处理后存活并抵抗 Sal 细胞毒性作用的细胞中，Akt 激活增加。综上所述，这些结果表明 Akt 激活可能促进癌细胞对 Sal 的耐药性。
