Prasad Nagendra K
Department of Basic Medical Sciences and Purdue Cancer Center, Purdue University, West Lafayette, IN 47907, USA.
Int J Oncol. 2009 Jan;34(1):97-105.
The phosphoinositol phosphatase SHIP2 is an important regulator of energy metabolism. SHIP2 dephosphorylates phosphatidylinositol 3,4,5 trisphosphates which are critical second messengers in signaling pathways induced by various extracellular stimuli including insulin. SHIP2 also regulates cytoskeleton remodeling, cell adhesion and spreading. In addition, endogenous SHIP2 in HeLa cells regulates receptor endocytosis and ligand-induced EGFR degradation. Further, SHIP2 in MDA-MB-231 breast cancer cells regulates EGFR levels and supports in vitro cell proliferation and in vivo tumor growth and spontaneous metastasis. Here we examine the role of SHIP2 in EGF signaling in breast cancer cells using RNA interference. Our results show that suppression of SHIP2 in MDA-MB-231 breast cancer cells alters EGF and EGFR internalization. Upon SHIP2 silencing, EGF-induced Akt activation was reduced causing decreased nuclear levels of activated Akt. Cytokine receptor CXCR4, a downstream element of EGFR-Akt pathway that plays an important role in metastasis, is down-regulated upon SHIP2 knockdown. Finally, cell adhesion and EGF-induced cell migration were suppressed in SHIP2 silenced cells. These results demonstrate a positive role of SHIP2 in EGF-induced Akt activation, CXCR4 expression, and cell migration in breast cancer cells.
磷酸肌醇磷酸酶SHIP2是能量代谢的重要调节因子。SHIP2使磷脂酰肌醇3,4,5-三磷酸去磷酸化，而磷脂酰肌醇3,4,5-三磷酸是包括胰岛素在内的各种细胞外刺激所诱导的信号通路中的关键第二信使。SHIP2还调节细胞骨架重塑、细胞黏附和铺展。此外，HeLa细胞中的内源性SHIP2调节受体胞吞作用和配体诱导的表皮生长因子受体（EGFR）降解。再者，MDA-MB-231乳腺癌细胞中的SHIP2调节EGFR水平，并支持体外细胞增殖以及体内肿瘤生长和自发转移。在此，我们使用RNA干扰研究SHIP2在乳腺癌细胞表皮生长因子（EGF）信号传导中的作用。我们的结果表明，抑制MDA-MB-231乳腺癌细胞中的SHIP2会改变EGF和EGFR的内化。SHIP2沉默后，EGF诱导的Akt激活减少，导致活化Akt的核水平降低。细胞因子受体CXCR4是EGFR-Akt途径的下游元件，在转移中起重要作用，在SHIP2敲低后其表达下调。最后，SHIP2沉默的细胞中细胞黏附和EGF诱导的细胞迁移受到抑制。这些结果证明了SHIP2在EGF诱导的乳腺癌细胞Akt激活、CXCR4表达和细胞迁移中发挥积极作用。
