Khalil Bassem D, Hsueh Christine, Cao Yanyan, Abi Saab Widian F, Wang Yarong, Condeelis John S, Bresnick Anne R, Backer Jonathan M
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York.
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York.
Cancer Res. 2016 May 15;76(10):2944-53. doi: 10.1158/0008-5472.CAN-15-1675. Epub 2016 Mar 24.
Inappropriate activation of PI3K signaling has been implicated strongly in human cancer. Although studies on the role of PI3K signaling in breast tumorigenesis and progression have focused most intensively on PI3Kα, a role for PI3Kβ has begun to emerge. The PI3Kβ isoform is unique among class IA PI3K enzymes in that it is activated by both receptor tyrosine kinases and G-protein-coupled receptors (GPCR). In previous work, we identified a mutation that specifically abolishes PI3Kβ binding to Gβγ (p110(526KK-DD)). Expression of this mutant in p110β-silenced breast cancer cells inhibits multiple steps of the metastatic cascade in vitro and in vivo and causes a cell autonomous defect in invadopodial matrix degradation. Our results identify a novel link between GPCRs and PI3Kβ in mediating metastasis, suggesting that disruption of this link might offer a novel therapeutic target to prevent the development of metastatic disease. Cancer Res; 76(10); 2944-53. ©2016 AACR.
PI3K信号通路的不适当激活与人类癌症密切相关。尽管关于PI3K信号通路在乳腺肿瘤发生和进展中的作用的研究主要集中在PI3Kα上，但PI3Kβ的作用也已开始显现。PI3Kβ亚型在IA类PI3K酶中是独特的，因为它可被受体酪氨酸激酶和G蛋白偶联受体（GPCR）激活。在先前的研究中，我们鉴定出一种特异性消除PI3Kβ与Gβγ结合的突变（p110(526KK-DD)）。在p110β沉默的乳腺癌细胞中表达这种突变体可在体外和体内抑制转移级联反应的多个步骤，并导致侵袭伪足基质降解出现细胞自主缺陷。我们的结果确定了GPCR与PI3Kβ在介导转移过程中的新联系，表明破坏这种联系可能提供一个预防转移性疾病发展的新治疗靶点。《癌症研究》；76(10)；2944 - 53。©2016美国癌症研究协会。
