Signaling cascades and apoptosis in prostate cancer cells


About the project

A related topic of interest in our laboratory is the molecular mechanisms of apoptosis, or programmed cell death, induced by androgen withdrawal in the normal prostate and early stage prostate cancer. This is at least in part at the basis for androgen ablation therapy in prostate cancer. Since it appears that in the later stages of prostate cancer the cells lose their apoptotic potential, it is important to understand the mechanisms of apoptosis; such knowledge may be useful in restoring the apoptotic potential of prostate cancer cells and thereby controlling their growth. To gain insight to this process, we have been studying the intracellular signaling cascades that may be involved in regulating apoptosis in prostate cancer cells. In particular, we focus on the activity and regulation of the mitogen activated protein kinase (MAPK) family and the phosphatases that regulate their activity, MAPK phosphatases or MKPs. Different components of the MAPK cascade have previously been implicated in the regulation of apoptosis, often with opposite consequences in different cell types. We found that there are distinct changes in the activity of one major MAPK pathway, the c-Jun N-terminal Kinase (JNK), but not other MAPK pathways, in the androgen responsive prostate cancer cells, but not in the androgen insensitive and apoptosis resistant prostate cancer cell lines. Blocking JNK inhibits apoptosis. Consistent with these findings, at least one MKP family member is downregulated during apoptosis of prostate cancer cells and its ectopic expression inhibits apoptosis. These findings suggest that programmed cell death in prostate cancer cells requires signaling through the JNK cascade, and at least in part regulated by VHR, that may be defective in the androgen independent cells. More detailed in vitro and in vivo studies are in progress.



Published Oct. 27, 2015 3:40 PM - Last modified June 8, 2016 9:16 PM
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