Prasad Nagendra K, Tandon Manish, Badve Sunil, Snyder Paul W, Nakshatri Harikrishna
Department of Basic Medical Sciences and Purdue Cancer Center, Purdue University, LYNN Hall, 625 Harrison Street, West Lafayette, IN 47907, USA.
Carcinogenesis. 2008 Jan;29(1):25-34. doi: 10.1093/carcin/bgm213. Epub 2007 Sep 24.
Phosphoinositol phosphatases are important regulators of signaling pathways relevant to both diabetes and cancer. A 3'-phosphoinositol phosphatase, phosphatase homologous to tensin (PTEN), is both a tumor suppressor and a negative regulator of insulin action. A 5'-phosphoinositol phosphatase, SH2-containing 5'-inositol phosphatase (SHIP2), regulates insulin signaling and its genetic knockout prevents high-fat diet-induced obesity in mice. SHIP2 also regulates cytoskeleton remodeling and receptor endocytosis. This and the fact that both PTEN and SHIP2 act on the same substrate suggest a potential role for SHIP2 in cancer. Here we report that, in direct contrast to PTEN, SHIP2 protein expression is elevated in a number of breast cancer cell lines. RNA interference-mediated silencing of SHIP2 in MDA-231 cells suppresses epidermal growth factor receptor (EGFR) levels by means of enhanced receptor degradation. Furthermore, endogenous SHIP2 in MDA-231 breast cancer cells supports in vitro cell proliferation, increases cellular sensitivity to drugs targeting the EGFR and supports cancer development and metastasis in nude mice. In addition, significantly high proportions (44%; P = 0.0001) of clinical specimens of breast cancer tissues in comparison with non-cancerous breast tissues contain elevated expression of SHIP2 protein. Taken together, our results demonstrate that SHIP2 is a clinically relevant novel anticancer target that links perturbed metabolism to cancer development.
磷酸肌醇磷酸酶是与糖尿病和癌症相关的信号通路的重要调节因子。一种3'-磷酸肌醇磷酸酶，张力蛋白同源磷酸酶（PTEN），既是一种肿瘤抑制因子，也是胰岛素作用的负调节因子。一种5'-磷酸肌醇磷酸酶，含SH2结构域的5'-肌醇磷酸酶（SHIP2），调节胰岛素信号传导，其基因敲除可预防小鼠高脂饮食诱导的肥胖。SHIP2还调节细胞骨架重塑和受体胞吞作用。这一点以及PTEN和SHIP2作用于同一底物这一事实表明SHIP2在癌症中可能发挥作用。在此我们报告，与PTEN形成直接对比的是，SHIP2蛋白表达在许多乳腺癌细胞系中升高。RNA干扰介导的MDA-231细胞中SHIP2沉默通过增强受体降解来抑制表皮生长因子受体（EGFR）水平。此外，MDA-231乳腺癌细胞中的内源性SHIP2支持体外细胞增殖，增加细胞对靶向EGFR药物 的敏感性，并支持裸鼠体内的癌症发展和转移。此外，与非癌性乳腺组织相比，乳腺癌组织临床标本中SHIP2蛋白表达显著升高的比例很高（44%；P = 0.0001）。综上所述，我们的结果表明SHIP2是一个与临床相关的新型抗癌靶点，它将代谢紊乱与癌症发展联系起来。
