Non-canonical Notch Signaling Regulates Actin Remodeling in Cell Migration by Activating PI3K/AKT/Cdc42 Pathway
Non-canonical Notch Signaling Regulates Actin Remodeling in Cell Migration by Activating PI3K/AKT/Cdc42 Pathway
复制标题
非经典 Notch 信号传导通过激活 PI3K/AKT/Cdc42 通路调节细胞迁移中的肌动蛋白重塑
DOI：
10.3389/fphar.2019.00370
复制
发表时间：
2019-04-16
影响因子：
5.6
通讯作者：
Gu, Luo
中科院分区：
文献类型：
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作者：
Liu, Lei;Zhang, Lin;Gu, Luo
肿瘤细胞迁移是肿瘤转移的关键步骤。Notch信号通路的过度激活会促进癌细胞的迁移，尤其是在乳腺癌中。然而，非经典Notch信号转导在调节迁移中的潜在机制尚未被明确表征。在这里，我们证明了γ分泌酶抑制剂DAPT通过非经典Notch途径增加Cdc 42的活性，抑制突起形成和细胞运动，从而减少三阴性乳腺癌细胞的迁移。当Notch信号被DAPT抑制时，S473上AKT的磷酸化令人惊讶地增加。分别用LY 294002和MK2206抑制PI 3 K和AKT，或用siRNA敲低AKT表达，可阻断DAPT诱导的Cdc 42活化。此外，免疫荧光染色进一步表明，DAPT处理减少了板状伪足的形成，并诱导肌动蛋白细胞骨架重塑。这些结果表明，DAPT通过非经典途径抑制Notch信号通路，进而激活PI 3 K/AKT/Cdc 42信号通路，促进丝状伪足的形成，抑制片状伪足的组装，最终导致乳腺癌细胞迁移活性降低。
Tumor cell migration is a critical step in cancer metastasis. Over-activated Notch pathway can promote the migration of cancer cells, especially in the breast cancer. However, the underlying mechanism of non-canonical Notch signaling in modulating the migration has not yet been clearly characterized. Here we demonstrated that DAPT, a gamma secretase inhibitor, inhibited protrusion formation and cell motility, and then reduced the migration of triple-negative breast cancer cells, through increasing the activity of Cdc42 by non-canonical Notch pathway. Phosphorylation of AKT on S473 was surprisingly increased when Notch signaling was inhibited by DAPT. Inhibition of PI3K and AKT by LY294002 and MK2206, respectively, or knockdown of AKT expression by siRNA blocked DAPT-induced activation of Cdc42. Moreover, immunofluorescence staining further showed that DAPT treatment reduced the formation of lamellipodia and induced actin cytoskeleton remodeling. Taken together, these results indicated that DAPT inhibited Notch signaling and consequently activated PI3K/AKT/Cdc42 signaling by non-canonical pathway, facilitated the formation of filopodia and inhibited the assembly of lamellipodia, and finally resulted in the decrease of migration activity of breast cancer cells.