Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
Biochem Biophys Res Commun. 2020 Jul 12;528(1):92-98. doi: 10.1016/j.bbrc.2020.05.043. Epub 2020 May 23.
The adaptive activation of alternative signaling pathways contributes to acquired resistance against targeted cancer therapies. Our previous research has shown that blocking Ras/ERK signaling promotes PI3K/AKT signaling in the lung metastatic derivative of MDA-MB-231 (LM2). Because AKT activation was required to drive sustained cell motility following MEK suppression, we extend our research to elucidate how activation of the PI3K/AKT signaling drives sustained motility following MEK inhibition. Reverse phase protein array (RPPA) revealed that SNAIL (SNAI1) was upregulated in U0126 (MEK inhibitor)-treated LM2 cells. Importantly, LM2 cells simultaneously treated with U0126 and PI3K inhibitor LY294002 exhibited reduced expression of SNAIL. Furthermore, depletion of SNAIL led to reduced cell motility in U0126-treated LM2 cells. In addition, we identified AXL as another downstream effector of AKT. These results suggest that SNAIL and AXL are key factors mediating sustained motility of LM2 cells following MEK suppression. Because AKT mediates motile behavior under MEK suppression, our results suggest that AKT and AXL may be targeted to overcome resistance against drugs targeting the Ras/ERK pathway.
适应性激活替代信号通路有助于获得针对癌症的靶向治疗的耐药性。我们之前的研究表明，阻断 Ras/ERK 信号会促进 MDA-MB-231（LM2）肺转移衍生细胞系中 PI3K/AKT 信号的激活。由于 AKT 的激活对于 MEK 抑制后持续的细胞迁移是必需的，我们进一步研究阐明了 PI3K/AKT 信号的激活如何在 MEK 抑制后驱动持续的迁移。反相蛋白阵列（RPPA）显示 U0126（MEK 抑制剂）处理的 LM2 细胞中 SNAIL（SNAI1）上调。重要的是，同时用 U0126 和 PI3K 抑制剂 LY294002 处理的 LM2 细胞中 SNAIL 的表达减少。此外，SNAIL 的耗竭导致 U0126 处理的 LM2 细胞中的细胞迁移减少。此外，我们确定了 AXL 是 AKT 的另一个下游效应物。这些结果表明，SNAIL 和 AXL 是介导 MEK 抑制后 LM2 细胞持续迁移的关键因素。由于 AKT 在 MEK 抑制下介导迁移行为，我们的结果表明 AKT 和 AXL 可能是针对 Ras/ERK 通路靶向药物的耐药性的潜在治疗靶点。
