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  • Title: Constitutive activation of P I3 K-Akt and NF-kappaB during prostate cancer progression in autochthonous transgenic mouse model.
    Author: Shukla S, Maclennan GT, Marengo SR, Resnick MI, Gupta S.
    Journal: Prostate; 2005 Aug 01; 64(3):224-39. PubMed ID: 15712212.
    Abstract:
    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 (P I3 K)-Akt and transcription factor NF-kappaB are important signaling molecules and key survival factors involved in the control of cell proliferation, apoptosis, and oncogenesis. Although P I3 K-Akt and NF-kappaB 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 P I3 K-Akt, NF-kappaB, I kappaB, 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 P I3 K, phosphorylated-Akt (Ser 473), I kappa Balpha and its phosphorylation, IKK kinase activity, NF-kappaB/p65, p50, DNA binding, and transcriptional-regulated genes, viz., Bc l2, 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 P I3 K-Akt, NF-kappaB and I kappaB during prostate cancer progression in TRAMP mice suggest that these molecules represent potential molecular targets for prevention and/or therapeutic intervention.
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