Constitutive activation of PI3K-Akt and NF-κB during prostate cancer progression in autochthonous transgenic mouse model
Constitutive activation of PI3K-Akt and NF-κB during prostate cancer progression in autochthonous transgenic mouse model
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DOI：
10.1002/pros.20217
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发表时间：
2005-08-01
期刊：
影响因子：
2.8
通讯作者：
Gupta, S
中科院分区：
文献类型：
--
作者：
Shukla, S;MacLennan, GT;Gupta, S
背景癌症进展通常由独立的生长信号促进，这可能导致细胞存活增加和凋亡逃避。磷脂酰肌醇3 '-OH激酶（PI 3 K）-Akt和转录因子NF-κ B是参与控制细胞增殖、凋亡和肿瘤发生的重要信号分子和关键存活因子。虽然PI 3 K-Akt和NF-κ B B参与了前列腺癌的发生和发展，但这些分子在原发性疾病进展过程中的表达尚未阐明。通过磁共振成像（MRI）观察小鼠前列腺原位转基因腺癌（TRAMP）小鼠和雄性非转基因同窝仔中前列腺癌的生长和进展。通过Western blot分析、电泳迁移率变动分析（EMSA）、酶联免疫吸附分析（ELISA）、激酶分析和免疫组化检测这些小鼠中PI 3 K-Akt、NF-κ B、11：13和相关信号分子在癌症进展的不同阶段的表达模式。前列腺的连续MRI和大体分析显示，与雄性非转基因同窝出生小鼠相比，TRAMP小鼠中前列腺体积增加与前列腺腺癌的发生和进展相关。PI 3 K、磷酸化Akt（Ser 473）、I κ B α及其磷酸化、IKK激酶活性、NF-κ B/p65、p50、DNA结合和转录调节基因的差异蛋白表达，通过与同窝出生的雄性非转基因小鼠相比，在TRAMP小鼠前列腺癌进展期间观察到Bcl 2、细胞周期蛋白D1、MMP-9和VEGF。这些分子的表达在24和32周龄时观察到的癌症进展过程中显著增加。TRAMP小鼠前列腺癌进展期间PI 3 K-Akt、NF-κ B和I κ B的差异表达模式表明这些分子代表预防和/或治疗干预的潜在分子靶标。(c)2005 Wiley-Liss Inc.
BACKGROUND. Cancer progression is usually facilitated by independent growth signals that may lead to increased cell survival and evasion of apoptosis. Phosphatidylinositol 3'-OH kinase (PI3K)-Akt and transcription factor NF-kappa B are important signaling molecules and key survival factors involved in the control of cell proliferation, apoptosis, and oncogenesis. Although PI3K-Akt and NF-kappa B have been implicated in the development and progression of prostate cancer, expression of these molecules during progression of autochthonous disease has not been elucidated.METHODS. Prostate cancer growth and progression in autochthonous transgenic adenocarcinoma of the mouse prostate (TRAMP) mice and male non-transgenic littermates were observed by magnetic resonance imaging (MRI). Expression patterns of PI3K-Akt, NF-kappa B, 11:13, and associated signaling molecules during different stages of cancer progression in these mice were examined by Western blot analysis, electrophoretic mobility shift assay (EMSA), enzyme-linked immunoabsorbent assay (ELISA), kinase assay, and immunohistochemistry,RESULTS. Sequential MRI and gross analysis of prostate gland exhibited increasing prostate volume associated with the development and progression of prostatic adenocarcinoma in TRAMP mice, compared to male non-transgenic littermates. Differential protein expression of PI3K, phosphorylated-Akt (Ser473), I kappa B alpha and its phosphorylation, IKK kinase activity, NF-kappa B/p65, p50, DNA binding, and transcriptional-regulated genes, via., Bcl2, cyclin D1, MMP-9, and VEGF were observed during prostate cancer progression in TRAMP mice, compared to male non-transgenic littermates. Expressions of these molecules were significantly increased during cancer progression observed at 24 and 32 weeks of age.CONCLUSIONS. Differential expression pattern of PI3K-Akt, NF-kappa B and I kappa B during prostate cancer progression in TRAMP mice suggest that these molecules represent potential molecular targets for prevention and/or therapeutic intervention. (c) 2005 Wiley-Liss Inc.