Miyamoto H, Altuwaijri S, Cai Y, Messing EM, Chang C.. Inhibition of the Akt, cyclooxygenase-2, and matrix metalloproteinase-9 pathways in combination with androgen deprivation therapy: potential therapeutic approaches for prostate cancer. Mol Carcinog 44: 1-10

Department of Pathology, University of Rochester Medical Center, Rochester, New York 14642, USA.
Molecular Carcinogenesis (Impact Factor: 4.81). 09/2005; 44(1):1-10. DOI: 10.1002/mc.20121
Source: PubMed


Prostate cancer cells are generally dependent on androgen stimulation mediated by the androgen receptor (AR) for growth and survival, and, therefore, hormonal manipulation, such as castration and/or the use of AR antagonists, results in a regression of the cancer. However, this treatment very rarely leads to the "cure" of advanced disease, and cancers eventually become androgen-independent. A number of genes/pathways have been reported to be activated in prostate cancer, most of which are possibly associated with disease progression. In this article, among them, we focus on Akt (also known as protein kinase B), cyclooxygenase (COX)-2, and matrix metalloproteinase (MMP)-9, whose activities or expressions have been found to be regulated by androgens/AR. Previous studies by us and others, with androgen-sensitive prostate cancer cell lines, have demonstrated that androgen deprivation results in activation/overexpression of Akt, COX-2, and MMP-9 in cells. This suggests that androgen deprivation in clinical settings activates the Akt, COX-2, and MMP-9 pathways in prostate cancer, which may increase cell growth and in turn promote the transition to the androgen-independent state. We hypothesize that androgen deprivation, in combination with inhibition of the Akt, COX-2, and MMP-9 pathways, delays the androgen-independent transition and has more beneficial effects than hormonal therapy alone.

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Available from: Saleh Altuwaijri
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    • "( ⁄ p < 0.05). et al., 2006; Miyamoto et al., 2005; Yoo et al., 2011), we also determined if relaxin activates Akt. We found that relaxin enhanced the phosphorylation of Akt, and that this phosphorylation was inhibited in the presence of PI3K inhibitor concurrent with the lack of induction of MMP-9 by the hormone (Fig. 6A and B). "
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    • "In effect, we arrived at a similar conclusion after examination of the expression of the serine–threonine kinase Akt. Akt functions as the central integrating module of the phosphatidylinositol 3-kinase – Akt signalling pathway in the cell and regulates a number of critical cellular pathways, including those leading to cellular proliferation and inhibition of apoptosis (Li et al. 2005; Miyamoto et al. 2005). Thus Akt plays an important role in maintaining cell survival (Datta, et al. 1999; Kandel and Hay 1999; Downward 2004). "
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    • "Activated AR moves into nucleus, binds to androgen response element (ARE) and regulates transcription of many target genes, such as Akt, cox-2, and mmp9 [8]. These genes are activated in prostate cancer and associated with cancer progression [9]. AR could be activated through cytokine or growth factor pathways in androgen-independent stage to promote cancer cell survival. "
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