| Abstract: |
Interleukin-6 (IL6) is a growth and survival factor in human prostate cancer (PCa) cells with aggressive phenotypes and has been implicated in the progression of hormone refractory PCas. In the present study, we characterized the IL6-triggered PI3K/Akt and MAPK/Erk signaling. We identified the A-type cyclin, cyclin A1 as an important downstream target of PI3K/Akt. Treatment of cells with PI3K inhibitor or cotransfection with a vector expressing wild-type PTEN decreased cyclin A1 promoter activity. Cyclin A1 promoter activity and its expression were upregulated by constitutively active myristoylated Akt and were downregulated by dominant negative Akt in response to IL6 stimulation. LNCaP cells overexpressing cyclin A1 are resistant to camptothecin-induced apoptosis. Conversely, targeted knockdown of cyclin A1 via shRNA in LNCaP IL6+ cells resulted in decreased survival after treatment with camptothecin. This suggests that cyclin A1 is an important downstream target of PI3K/Akt that transduces survival signals in response to IL6 stimulation. Xenograft tumors generated from LNCaP-IL6+ cells expressing IL6 had higher levels of cyclin A1 and had rapid tumor growth compared to LNCaP xenograft tumors. Taken together, IL6 might utilize PI3K/Akt and cyclin A1 to promote tumor cell survival in PCa. © 2007 Wiley-Liss, Inc. |
| Keywords: |
signal transduction; survival; mitogen activated protein kinase; protein kinase b; protein expression; unclassified drug; human cell; pathophysiology; antineoplastic agent; metabolism; cell survival; apoptosis; mitogen activated protein kinase kinase 1; mitogen activated protein kinase kinase 2; antineoplastic agents, phytogenic; camptothecin; down-regulation; drug effect; transfection; wild type; phosphatidylinositol 3 kinase; prostate cancer; prostatic neoplasms; gene expression regulation; gene expression regulation, neoplastic; genetic transfection; xenograft; cancer cell; prostate tumor; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; 1-phosphatidylinositol 3-kinase; proto-oncogene proteins c-akt; pten phosphohydrolase; plasmid; immunoblotting; transplantation, heterologous; interleukin 6; interleukin-6; plasmids; down regulation; upregulation; up-regulation; tumor growth; cell stimulation; cyclin a; signal processing; pten protein, human; short hairpin rna; map kinase kinase 1; map kinase kinase 2; protein kinase b inhibitor; cyclin a1; myristylation; pi3k/akt signaling; ccna1 protein, human
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