Duckworth C, Zhang L, Carroll S L, Ethier S P, Cheung H W
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, USA.
Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA.
Oncogene. 2016 Aug 4;35(31):4036-47. doi: 10.1038/onc.2015.472. Epub 2015 Dec 14.
We previously found that the scaffold adapter GRB2-associated binding protein 2 (GAB2) is amplified and overexpressed in a subset of primary high-grade serous ovarian cancers and cell lines. Ovarian cancer cells overexpressing GAB2 are dependent on GAB2 for activation of the phosphatidylinositol 3-kinase (PI3K) pathway and are sensitive to PI3K inhibition. In this study, we show an important role of GAB2 overexpression in promoting tumor angiogenesis by upregulating expression of multiple chemokines. Specifically, we found that suppression of GAB2 by inducible small hairpin RNA in ovarian cancer cells inhibited tumor cell proliferation, angiogenesis and peritoneal tumor growth in immunodeficient mice. Overexpression of GAB2 upregulated the secretion of several chemokines from ovarian cancer cells, including CXCL1, CXCL2 and CXCL8. The secreted chemokines not only signal through endothelial CXCR2 receptor in a paracrine manner to promote endothelial tube formation, but also act as autocrine growth factors for GAB2-induced transformation of fallopian tube secretory epithelial cells and clonogenic growth of ovarian cancer cells overexpressing GAB2. Pharmacological inhibition of inhibitor of nuclear factor kappa-B kinase subunit β (IKKβ), but not PI3K, mechanistic target of rapamycin (mTOR) or mitogen-activated protein kinase (MEK), could effectively suppress GAB2-induced chemokine expression. Inhibition of IKKβ augmented the efficacy of PI3K/mTOR inhibition in suppressing clonogenic growth of ovarian cancer cells with GAB2 overexpression. Taken together, these findings suggest that overexpression of GAB2 in ovarian cancer cells promotes tumor growth and angiogenesis by upregulating expression of CXCL1, CXCL2 and CXCL8 that is IKKβ-dependent. Co-targeting IKKβ and PI3K pathways downstream of GAB2 might be a promising therapeutic strategy for ovarian cancer that overexpresses GAB2.
我们之前发现，支架衔接蛋白生长因子受体结合蛋白2相关结合蛋白2（GAB2）在一部分原发性高级别浆液性卵巢癌及细胞系中存在扩增和过表达。过表达GAB2的卵巢癌细胞激活磷脂酰肌醇3激酶（PI3K）通路依赖于GAB2，并且对PI3K抑制敏感。在本研究中，我们展示了GAB2过表达在通过上调多种趋化因子的表达促进肿瘤血管生成方面的重要作用。具体而言，我们发现用可诱导的小发夹RNA抑制卵巢癌细胞中的GAB2可抑制免疫缺陷小鼠体内的肿瘤细胞增殖、血管生成及腹膜肿瘤生长。GAB2的过表达上调了卵巢癌细胞中几种趋化因子的分泌，包括CXCL1、CXCL2和CXCL8。分泌的趋化因子不仅以旁分泌方式通过内皮细胞CXCR2受体发出信号以促进内皮管形成，还作为自分泌生长因子促进GAB2诱导的输卵管分泌上皮细胞转化以及过表达GAB2的卵巢癌细胞的克隆生长。对核因子κB激酶亚基β（IKKβ）抑制剂而非PI3K、雷帕霉素靶蛋白（mTOR）或丝裂原活化蛋白激酶（MEK）的药理学抑制可有效抑制GAB2诱导的趋化因子表达。抑制IKKβ增强了PI3K/mTOR抑制在抑制过表达GAB2的卵巢癌细胞克隆生长方面的疗效。综上所述，这些发现表明卵巢癌细胞中GAB2的过表达通过上调依赖于IKKβ的CXCL1、CXCL2和CXCL8的表达促进肿瘤生长和血管生成。共同靶向GAB2下游的IKKβ和PI3K通路可能是过表达GAB2的卵巢癌的一种有前景的治疗策略。
