Constitutive activation of PI3K-Akt and NF-κB during prostate cancer progression in autochthonous transgenic mouse model

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 (PI3K)-Akt and transcription factor NF-κB are important signaling molecules and key survival factors involved in the control of cell proliferation, apoptosis, and oncogenesis. Although PI3K-Akt and NF-κB 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-κB, IκB, 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), IκBα and its phosphorylation, IKK kinase activity, NF-κB/p65, p50, DNA binding, and transcriptional-regulated genes, viz., 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-κB and IκB during prostate cancer progression in TRAMP mice suggest that these molecules represent potential molecular targets for prevention and/or therapeutic intervention.