Modulation of Intracellular Signaling Pathways to Induce Apoptosis in Prostate Cancer Cells

Abstract

An understanding of the molecular pathways defining the susceptibility of prostate cancer, especially refractory prostate cancer, to apoptosis is the key for developing a cure for this disease. We previously demonstrated that up-regulating Ras signaling, together with suppression of protein kinase C (PKC), induces apoptosis. Dysregulation of various intracellular signaling pathways, including those governed by Ras, is the important element in the development of prostate cancer. In this study, we tested whether it is possible to modulate the activities of these pathways and induce an apoptotic crash among them in prostate cancer cells. Our data showed that DU145 cells express a high amount of JNK1 that is phosphorylated after endogenous PKC is suppressed, which initiates caspase 8 cleavage and cytochrome c release, leading to apoptosis. PC3 and LNCaP cells contain an activated Akt. The inhibition of PKC further augments Akt activity, which in turn induces ROS production and the accumulation of unfolded proteins in the endoplasmic reticulum, resulting in cell death. However, the concurrent activation of JNK1 and Akt, under the condition of PKC abrogation, dramatically augment the magnitude of apoptosis in the cells. Thus, our study suggests that Akt, JNK1, and PKC act in concert to signal the intracellular apoptotic machinery for a full execution of apoptosis in prostate cancer cells.It has been well documented that oncogenes (such as myc or ras) and their downstream effectors cannot only promote cell growth, but also, under certain circumstances, elicit programmed cell death or apoptosis (1-4). Mutational activation of the Ras gene is a key event in human cancer development (5-10). In the process of transformation, a persistent increase in Ras activity up-regulates its downstream effector pathways, leading to the phosphorylation and activation of pro-growth transcriptional factors (5-10). Despite its central involvement in cell growth and differentiation, we and others have demonstrated that treatment with PKC 2 inhibitors can induce apoptosis in various types of cells overexpressing oncogenic v-Ha or . In addition, stress-related kinases, such as c-Jun kinase (JNK)/p38 functions as Ras downstream effectors to initiate apoptosis (4).Ras governs multiple downstream effector pathways, such as Raf/MAP/ERK, PI3K/Akt, JNK/p38, and RalGSD (5-10). In response to mitogenic stimulation, Ras is activated, which in turn causes the plasma membrane translocation of the Raf/ MAPK/ERK cascade, resulting in phosphorylation of transcription factors and other proteins (17,18). The activation of PI3K or RalGDS has been suggested to be involved in the regulation of the rearrangement of cytoskeleton to promote growth-related signal transduction (19 -23). Furthermore, it has been demonstrated that in response to PKC inhibition, JNK1 acts as an intermediator to redirect Ras-mediated signaling for the initiation of caspase cascade (16). However, the suppression of JNK1 only partially blocked the apoptotic process, indicating that other ...

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