Targeting prostate cancer based on signal transduction and cell cycle pathways - PubMed (original) (raw)

Review

. 2008 Jun 15;7(12):1745-62.

doi: 10.4161/cc.7.12.6166. Epub 2008 Jun 16.

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Review

Targeting prostate cancer based on signal transduction and cell cycle pathways

John T Lee et al. Cell Cycle. 2008.

Abstract

Prostate cancer remains a leading cause of death in men despite increased capacity to diagnose at earlier stages. After prostate cancer has become hormone independent, which often occurs after hormonal ablation therapies, it is difficult to effectively treat. Prostate cancer may arise from mutations and dysregulation of various genes involved in regulation signal transduction (e.g., PTEN, Akt, etc.,) and the cell cycle (e.g., p53, p21(Cip1), p27(Kip1), Rb, etc.,). This review focuses on the aberrant interactions of signal transduction and cell cycle genes products and how they can contribute to prostate cancer and alter therapeutic effectiveness.

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Figures

Figure 1

Figure 1

Overview of PI3K/PTEN/Akt/mTOR Pathway. The PI3K/PTEN/Akt/mTOR pathway is regulated by Ras as well as various kinases. The PI3K/PTEN/Akt/mTOR pathway is also activated after receptor ligation. The PTEN phosphatase (black octagon) inhibits activation of PI3K. Downstream of PI3K, Akt has many downstream targets that regulate cell growth and apoptosis. The transcription factors regulated by these pathways are indicated in diamond-shaped outlines. Dotted lines in front of AAA indicate that there is suppression of expression of some genes due to Akt phosphorylation of transcription factors such as Foxo3. Some of the interactions between the PI3K/PTEN/Akt/mTOR and Raf/MEK/ERK pathways are also indicated.

Figure 2

Figure 2

Overview of Raf/MEK/ERK Pathway. The Raf/MEK/ERK pathway is regulated by Ras as well as various kinases (PKC, PAK, PKA). Many kinases serve to phosphorylate S/T and Y residues on Raf. Some of these phosphorylation events serve to enhance Raf activity (black P in a white circle) whereas others serve to inhibit Raf activity (white P in a black circle. Moreover there are phosphatases such as PP2A, which remove phosphates on certain regulatory residues. The downstream transcription factors regulated by this pathway are indicated in diamond-shaped outlines. Raf can also exert effects which are independent of MEK/ERK and can interact with mitochondrial proteins to regulate apoptosis.

Figure 3

Figure 3

Interactions Between PI3K/PTEN/Akt/mTOR, Raf/MEK/ERK and Cell Cycle Pathways in Prostate Cancer. All of these pathways interact to regulate the induction of cell cycle progression and apoptosis. The Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways normally serve to suppress apoptosis while p53, which is induced by certain chemotherapeutic drugs and ionizing radiation, will result in increases in pro-apoptotic family members and in some cases, growth factors which may activate certain growth factor receptors. p53 can also regulate the transcription of many genes including p21Cip-1, Bax, Puma, Noxa and other genes which serve to regulate cell cycle progression and the induction of apoptosis. Furthermore, p53 activity can be altered by phosphorylation by ERK as well as MDM2 levels, whose activity is in turn previously regulated by Akt. Hence these pathways are interconnected and serve to regulate each other.

Figure 4

Figure 4

Sites of Mutation which can Result in Altered PI3K/PTEN/Akt/mTOR Raf/MEK/ERK and Cell Cycle Pathways in Prostate Cells. Mutations and deletions have been detected in p53, PTEN, Rb, AR and many other genes in prostate cancer. Many of these mutations and chromosomal trans-locations result in activation or inactivation of the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR cascades as well as pathways which control cell cycle progression and apoptosis. The most frequently mutated genes are indicated by a starburst symbol.

Figure 5

Figure 5

Effects of PTEN and p53 Inactivation on PI3K/PTEN/Akt/mTOR and Raf/MEK/ERK Activation in Prostate Cancer. Some of the complex interactions between the PI3K/PTEN/ Akt/mTOR, Raf/MEK/ERK, p53 and cell cycle pathways and how they influence cell cycle progression in prostate cancer are presented.

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