PEA-15 unphosphorylated at both serine 104 and serine 116 inhibits ovarian cancer cell tumorigenicity and progression through blocking β-catenin.
PEA-15 unphosphorylated at both serine 104 and serine 116 inhibits ovarian cancer cell tumorigenicity and progression through blocking β-catenin.
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PEA-15在丝氨酸104和丝氨酸116上均未磷酸化可通过阻断β-catenin抑制卵巢癌细胞的肿瘤性和进展。
DOI：
10.1038/oncsis.2012.22
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发表时间：
2012-07-16
期刊：
影响因子：
6.2
通讯作者：
Ueno, N. T.
中科院分区：
文献类型：
--
作者：
Lee, J.;Bartholomeusz, C.;Krishnamurthy, S.;Liu, P.;Saso, H.;LaFortune, T. A.;Hortobagyi, G. N.;Ueno, N. T.
关键词：
卵巢癌是妇女死亡的主要原因;仍然迫切需要开发针对这种癌症的新的有效疗法。星形胶质细胞中富集的磷蛋白（PEA-15）是一种15 kDa的磷蛋白，已知其结合ERK 1/2，从而阻断细胞增殖。PEA-15的生理活性取决于丝氨酸104（Ser 104）和Ser 116的磷酸化状态。然而，关于PEA-15磷酸化对肿瘤进展的影响知之甚少。我们先前已经证明PEA-15的过表达对乳腺癌和卵巢癌细胞都具有抗肿瘤作用。在这里，我们报告说，使用人类卵巢癌组织微阵列，我们发现，卵巢癌患者的组织比相邻的正常组织更有可能表达PEA-15磷酸化在这两个网站。利用PEA-15的拟磷酸化和非磷酸化突变体，我们发现突变的双非磷酸化PEA-15，其中Ser 104和Ser 116被丙氨酸取代（PEA-15-AA）比拟磷酸化PEA-15，其中Ser 104和Ser 116被天冬氨酸取代（PEA-15-DD）在卵巢癌中具有更有效的抗肿瘤作用。此外，我们观察到PEA-15-AA的抗肿瘤作用是抑制细胞迁移能力和抑制体内血管生成的结果。这种抑制部分依赖于β-catenin表达和核转位的抑制。总之，我们的结果表明，磷酸化PEA-15是卵巢癌侵袭性的重要贡献者，并证明PEA-15-AA作为卵巢癌治疗中的有效治疗分子的发展是合理的。
Ovarian cancer is a major cause of death among women; there remains an urgent need to develop new effective therapies to target this cancer. Phosphoprotein enriched in astrocytes (PEA-15) is a 15-kDa phosphoprotein that is known to bind ERK1/2, thus blocking cell proliferation. The physiological activity of PEA-15 is dependent on the phosphorylation status of serine 104 (Ser104) and Ser116. However, little is known about the impact of PEA-15 phosphorylation on tumor progression. We have previously shown that overexpression of PEA-15 has an antitumor effect against both breast and ovarian cancer cells. Here, we report that using a human ovarian cancer tissue microarray, we found that tissues from patients with ovarian cancer were significantly more likely than adjacent normal tissues to express PEA-15 phosphorylated at both sites. Using phosphomimetic and nonphosphorylatable mutants of PEA-15, we found that mutant double-unphosphorylated PEA-15 in which Ser104 and Ser116 were substituted with alanine (PEA-15-AA) had a more potent antitumorigenic effect in ovarian cancer than did phosphomimetic PEA-15 in which Ser104 and Ser116 were substituted with aspartic acid (PEA-15-DD). Further, we observed that the antitumorigenic effect of PEA-15-AA was a result of inhibition of the migration capacity of cells and inhibition of in vivo angiogenesis. This inhibition was partially dependent on inhibition of β-catenin expression and nuclear translocalization. Taken together, our results suggest that phosphorylated PEA-15 is an important contributor to the aggressiveness of ovarian cancer and justify the development of PEA-15-AA as an effective therapeutic molecule in the treatment of ovarian cancer.
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影响因子：
11.2
作者：
Bartholomeusz C;Rosen D;Wei C;Kazansky A;Yamasaki F;Takahashi T;Itamochi H;Kondo S;Liu J;Ueno NT
通讯作者：
Ueno NT
PED/PEA-15与67 KD层粘连蛋白受体相互作用，并调节细胞粘附，迁移，增殖和凋亡。
影响因子：
5.3
作者：
Formisano P;Ragno P;Pesapane A;Alfano D;Alberobello AT;Rea VE;Giusto R;Rossi FW;Beguinot F;Rossi G;Montuori N
通讯作者：
Montuori N
影响因子：
56.9
作者：
Cukierman, E;Pankov, R;Yamada, KM
通讯作者：
Yamada, KM
影响因子：
2.7
作者：
Cheadle, Chris;Nesterova, Maria;Cho-Chung, Yoon S.
通讯作者：
Cho-Chung, Yoon S.
影响因子：
4.8
作者：
Boeck, Barbara C.;Tagscherer, Katrin E.;Roth, Wilfried
通讯作者：
Roth, Wilfried