PI(3,4)P(2) plays critical roles in the regulation of focal adhesion dynamics of MDA-MB-231 breast cancer cells.
PI(3,4)P(2) plays critical roles in the regulation of focal adhesion dynamics of MDA-MB-231 breast cancer cells.
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DOI：
10.1111/cas.13215
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发表时间：
2017-05
期刊：
影响因子：
5.7
通讯作者：
Takenawa T
中科院分区：
文献类型：
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作者：
Fukumoto M;Ijuin T;Takenawa T
磷酸肌醇在癌细胞表型的调节中发挥着关键作用。其中，磷脂酰肌醇3,4-二磷酸（PI(3,4)P2）定位于侵袭伪足，并正向调节肿瘤细胞侵袭。在这项研究中，我们研究了 PI(3,4)P2 对 MDA-MB-231 基底乳腺癌细胞粘着斑动力学的影响。在 MDA-MB-231 乳腺癌细胞中，SHIP2（一种生成 PI(3,4)P2 的磷脂酰肌醇 3,4,5-三磷酸酶 (PIP 3) 5-磷酸酶）的敲除可诱导粘着斑和细胞扩散的发展，从而抑制侵袭。相反，PTEN（一种使 PIP 3 和 PI(3,4)P2 去磷酸化的 3-磷酸酶）的敲除可诱导细胞收缩并增加细胞侵袭。有趣的是，额外敲除 SHIP2 可以挽救这些表型。与 PI(3,4)P2 结合的 TAPP1 PH 结构域的过表达以及 PI(3,4)P2 下游效应子 Lpd 的敲低，导致与 SHIP2 敲低所诱导的表型相似。综上所述，我们的结果表明，抑制 PI(3,4)P2 生成和/或下游信号传导可能有助于抑制乳腺癌转移。
Phosphoinositides play pivotal roles in the regulation of cancer cell phenotypes. Among them, phosphatidylinositol 3,4‐bisphosphate (PI(3,4)P2) localizes to the invadopodia, and positively regulates tumor cell invasion. In this study, we examined the effect of PI(3,4)P2 on focal adhesion dynamics in MDA‐MB‐231 basal breast cancer cells. Knockdown of SHIP2, a phosphatidylinositol 3,4,5‐trisphosphatase (PIP 3) 5‐phosphatase that generates PI(3,4)P2, in MDA‐MB‐231 breast cancer cells, induced the development of focal adhesions and cell spreading, leading to the suppression of invasion. In contrast, knockdown of PTEN, a 3‐phosphatase that de‐phosphorylates PIP 3 and PI(3,4)P2, induced cell shrinkage and increased cell invasion. Interestingly, additional knockdown of SHIP2 rescued these phenotypes. Overexpression of the TAPP1 PH domain, which binds to PI(3,4)P2, and knockdown of Lpd, a downstream effector of PI(3,4)P2, resulted in similar phenotypes to those induced by SHIP2 knockdown. Taken together, our results suggest that inhibition of PI(3,4)P2 generation and/or downstream signaling could be useful for inhibiting breast cancer metastasis.