Serum deprivation confers the MDA-MB-231 breast cancer line with an EGFR/JAK3/PLD2 system that maximizes cancer cell invasion.
Serum deprivation confers the MDA-MB-231 breast cancer line with an EGFR/JAK3/PLD2 system that maximizes cancer cell invasion.
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DOI：
10.1016/j.jmb.2012.11.035
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发表时间：
2013-02-22
影响因子：
5.6
通讯作者：
Gomez-Cambronero, Julian
中科院分区：
文献类型：
--
作者：
Ye, Qing;Kantonen, Samuel;Gomez-Cambronero, Julian
我们的实验室早些时候报道，在白细胞中，磷脂酶D2（PLD 2）受介导趋化性的Janus激酶-3（JAK 3）的控制。研究癌细胞中的JAK 3导致了一个重要的发现，因为指数生长的MDA-MB-231人乳腺癌细胞（其具有高度增殖性和转移性）基本上不使用JAK 3来激活PLD 2。然而，在2小时或16小时饥饿的细胞培养物中，JAK 3切换到PLD 2增强作用，这与那些细胞进入依赖于PLD 2活性增加以耐受血清剥夺的“存活状态”的需要一致。使用小分子酪氨酸激酶抑制剂类黄酮芹菜素（4 '，5，7-三羟基黄酮）以及RNA沉默，我们发现MDA-MB-231细胞的侵袭表型由PLD 2在JAK 3和酪氨酸激酶表皮生长因子受体（EGFR）两者的直接调节下介导。此外，培养物中的血清剥夺细胞显示上调的EGFR/JAK 3/PLD 2-PA系统，并且对JAK 3和PLD 2酶活性抑制剂的组合（分别为30 nM芹菜素和300 nM 5-氟-2-吲哚基脱氯卤代酰胺[FIPI]）特别敏感。因此，两种激酶（EGFR和JAK 3）和磷脂酶（PLD 2）对细胞侵袭的多层激活提供了调节灵活性，并使MDA-MB-231乳腺癌细胞的侵袭能力最大化。这在血清中缺乏生长因子的情况下尤其重要，与这些细胞迁移到新的位置相一致。
Our laboratory has reported earlier that in leukocytes, phospholipase D2 (PLD2) is under control of Janus Kinase-3 (JAK3), which mediates chemotaxis. Investigating JAK3 in cancer cells led to an important discovery as exponentially growing MDA-MB-231 human breast cancer cells, which are highly proliferative and metastatic, did not substantially use JAK3 to activate PLD2. However, in 2-h or 16-h starved cell cultures, JAK3 switches to a PLD2-enhancing role, consistent with the needs of those cells to enter a “survival state” that relies on an increase in PLD2 activity to withstand serum deprivation. Using a small-molecule tyrosine kinase inhibitor, the flavonoid apigenin (4’,5,7-trihydroxyflavone), as well as RNA silencing, we found that the invasive phenotype of MDA-MB-231 cells is mediated by PLD2 under direct regulation of both JAK3 and the tyrosine kinase, Epidermal Growth Factor Receptor (EGFR). Further, serum-deprived cells in culture show an upregulated EGFR/JAK3/PLD2-PA system and are especially sensitive to a combination of JAK3 and PLD2 enzymatic activity inhibitors (30 nM apigenin and 300 nM 5-Fluoro-2-Indolyl des-Chlorohalopemide [FIPI], respectively). Thus, a multi-layered activation of cell invasion by two kinases (EGFR and JAK3) and a pholspholipase (PLD2) provides regulatory flexibility and maximizes the aggressively invasive power of MDA-MB-231 breast cancer cells. This is especially important in the absence of growth factors in serum, coincidental with migration of these cells to new locations.
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