PEA-15 induces autophagy in human ovarian cancer cells and is associated with prolonged overall survival.
PEA-15 induces autophagy in human ovarian cancer cells and is associated with prolonged overall survival.
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DOI：
10.1158/0008-5472.can-08-2592
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发表时间：
2008-11-15
期刊：
影响因子：
11.2
通讯作者：
Ueno NT
中科院分区：
文献类型：
--
作者：
Bartholomeusz C;Rosen D;Wei C;Kazansky A;Yamasaki F;Takahashi T;Itamochi H;Kondo S;Liu J;Ueno NT
星形胶质细胞中的磷酸富集蛋白(PEA-15)是一种15 kDa的磷酸蛋白，通过与胞外信号调节激酶(ERK)结合并将其隔离在细胞质中，从而抑制ERK依赖的转录和增殖，从而减缓细胞的增殖。在以往对E1a人卵巢癌基因治疗的研究中，我们发现PEA-15通过将激活的ERK滞留在癌细胞的胞浆中，从而诱导E1a的抗肿瘤作用。在这里，我们研究了PEA-15在卵巢癌发生中的作用，PEA-15在人卵巢癌中的表达水平，以及PEA-15的表达是否与卵巢癌女性患者的总体生存相关。我们在低表达PEA-15的细胞中过表达PEA-15，在高表达PEA-15的细胞中下调PEA-15，并分析其对细胞增殖、锚定非依赖性生长和细胞周期进程的影响。然后，我们评估了395名原发性卵巢上皮癌患者肿瘤样本的注释组织微阵列中PEA-15的表达，并测试了PEA-15的表达是否与总生存率有关。PEA-15的表达抑制了细胞的增殖，细胞周期分析没有发现细胞凋亡，但确实发现了自噬，这一点从Lc3裂解的增加得到证实。抑制ERK1/2通路可减少PEA-15诱导的自噬。这些发现表明，PEA-15的抗肿瘤活性部分是通过诱导ERK1/2途径激活的自噬来实现的。多变量分析显示，PEA-15高表达的女性比PEA-15低表达的女性存活时间更长(风险比=1.973，P=0.0167)。我们的研究结果表明，PEA-15的表达是判断卵巢癌预后的重要指标。
Phospho-enriched protein in astrocytes (PEA-15) is a 15-kDa phosphoprotein that slows cell proliferation by binding to and sequestering extracellular signal-regulated kinase (ERK) in the cytoplasm, thereby inhibiting ERK-dependent transcription and proliferation. In previous studies of E1A human gene therapy for ovarian cancer, we discovered that PEA-15 induced the antitumor effect of E1A by sequestering activated ERK in the cytoplasm of cancer cells. Here, we investigated the role of PEA-15 in ovarian cancer tumorigenesis, the expression levels of PEA-15 in human ovarian cancer, and whether PEA-15 expression correlated with overall survival in women with ovarian cancer. We overexpressed PEA-15 in low-PEA-15-expressing cells and knocked down PEA-15 in high-PEA-15-expressing cells and analyzed the effect on proliferation, anchorage-independent growth, and cell cycle progression. We then assessed PEA-15 expression in an annotated tissue microarray of tumor samples from 395 women with primary epithelial ovarian cancer and tested whether PEA-15 expression was linked with overall survival. PEA-15 expression inhibited proliferation, and cell cycle analysis did not reveal apoptosis but did reveal autophagy, which was confirmed by an increase in LC3 cleavage. Inhibition of the ERK1/2 pathway decreased PEA-15-induced autophagy. These findings suggested that the antitumor activity of PEA-15 is mediated in part by the induction of autophagy involving activation of the ERK1/2 pathway. Multivariable analyses indicated that the women with high-PEA-15-expressing tumors survived longer than those with low-PEA-15-expressing tumors (hazard ratio = 1.973, P = 0.0167). Our findings indicate that PEA-15 expression is an important prognostic marker in ovarian cancer.