Mitogen Activated Protein kinase signal transduction pathways in the prostate

Cell Communication and Signaling Mitogen Activated Protein kinase signal transduction pathways in the prostate Paul D Maroni 0 1 Sweaty Koul 0 1 Randall B Meacham 0 Hari K Koul 0 1 0 Division of Urology, Department of Surgery, University of Colorado School of Medicine , 4200 East Ninth Avenue, C-319, Denver, CO 80262 , USA 1 Signal Transduction and Molecular Biology Laboratory, Division of Urology, Department of Surgery, University of Colorado School of Medicine , 4200 East Ninth Avenue, C-319, Denver, CO 80262 , USA The biochemistry of the mitogen activated protein kinases ERK, JNK, and p38 have been studied in prostate physiology in an attempt to elucidate novel mechanisms and pathways for the treatment of prostatic disease. We reviewed articles examining mitogen-activated protein kinases using prostate tissue or cell lines. As with other tissue types, these signaling modules are links/ transmitters for important pathways in prostate cells that can result in cellular survival or apoptosis. While the activation of the ERK pathway appears to primarily result in survival, the roles of JNK and p38 are less clear. Manipulation of these pathways could have important implications for the treatment of prostate cancer and benign prostatic hypertrophy. - MAP kinasesprostate cancerandrogenmitogen Background Signal transduction via mitogen activated protein (MAP) kinases plays a key role in a variety of cellular responses, including proliferation, differentiation, and cell death. MAP kinases have provided a focal point for remarkably rapid advances in our understanding of the control of cellular events by growth factors and stresses. Since their initial discovery in yeast, over a dozen MAP kinase families have been identified of these highly genetically conserved proteins. MAP kinase signal transduction pathways have not been studied in great detail in the prostate; however over one hundred publications describing the effects of various manipulations, including growth factors, chemical modifiers and androgens on prostatic cells have been described in the literature. Despite these studies, the structure and function of the MAP kinase pathways in prostate are far from clearly understood. Diseases of the prostate are a tremendous source of morbidity and mortality in aging males. Benign enlargement of the prostate gland is a significant source of discomfort and prostate cancer is the second leading cause of cancer related deaths in males. Most of the prostate cancer deaths result from emergence of an androgen resistant phenotype of prostate cancer. Unfortunately, treatment options for these androgen resistant prostate cancer patients are few and generally ineffective. These facts underline the need to develop new therapies that will improve outlook for hormone-independent prostate cancer. Several lines of evidence suggest a role for MAP kinase signal transduction pathways in prostate cancer. Here we provide a comprehensive review of studies specifically using prostate tissue or cell lines. Admittedly, many more publications may have examined some aspect of MAPKs, but we focused on abstracts including MAPK, ERK, JNK, or p38. The three major MAP kinase (MAPK) pathways include the extracellular-signal regulated kinase (ERK, also known as p42/44 MAP kinase), c-jun N-terminal kinase (JNK, also known as stress activated protein kinase-1 (SAPK1)) and p38 MAPK (also known as SAPK2/RK). In general, ERK1 and ERK2 are key transducers of proliferation signals and are often activated by mitogens. In contrast, SAPKs/JNKs and p38 are poorly activated by mitogens but strongly activated by cellular stress inducers. After activation, these cytosolic proteins translocate to the nucleus to activate numerous proteins and/or transcription factors. Each MAPK cascade consists of a core MAPK module, which has no less than three enzymes activated in series: 1) a MAPK, 2) an immediate upstream kinase (Known as Mitogen Activated Protein Kinase Kinase or MAPKK), and 3) an additional kinase upstream of the MAPKK (Known as Mitogen Activated Protein Kinase Kinase Kinase or MAPKKK). These regulatory cascades not only convey information to the target effectors, but also coordinate incoming information from parallel signaling pathways. These mechanisms allow for signal amplification and generate a threshold subject to multiple activation cascades. Then there are elements upstream of the core module. The interactions between MAP kinase and its immediate upstream kinase (MAPKK) are highly specific: for instance, p42/p44 MAP kinases are phosphorylated solely by MAP/ERK kinase (MEK) 1 and 2; p38 MAP kinase is selectively activated by MAP kinase kinases (MKK) 3 and 6, while JNK is activated by MKK7 and MKK4 in most conditions, however MKK4 can sometimes activate p38 MAP kinase when over expressed. The specificity is less clearly defined for elements upstream of the MAPKK modular level. For instance MAPKKK are highly promiscuous and can interact with and activate a number of down stream components. Similarly, signaling cross talk in the transmission levels between the mitogen/stress activator and the core MAPK module understandably adds more complexity to subtle differences in response despite equivalent activation. The specificity upstream of the core module may be regulated by additional components like scaffold proteins that help bring the specific components of the MAPK machinery together or keep various components from interacting with each other. A simplistic view of the MAP kinase signal transduction is presented in Figure 1. p42/p44 MAP kinase and the prostate Expression and activation of p42/p44 MAP kinase in tissue In normal noncancerous tissue from radical prostatectomy specimens, immunohistochemistry localizes ERK to the cytoplasm of most cells of the prostate including the epithelial, basal, and stromal cells [1,2]. Despite the abundance of ERK it does not appear to be active in the epithelial layer of normal prostatic tissue, but up to 80% of cells in the stroma and basal layers will stain positively for phosphorylated ERK (p-ERK) within the nucleus [3]. Gioeli et al also described p-ERK staining in normal prostate tissue adjacent to areas of prostate cancer and found that ERK activation was directly related to poor histologic/ prognostic features [4]. Nearly all studies involving this pathway have been examined using prostate cancer cell lines. There are 40 prostate cell lines available in the ATCC catalog of both normal and cancerous tissue. The most commonly used cell lines are the androgen sensitive LNCaP cells, isolated from a cancerous supraclavicular lymph node, and the androgen insensitive cell lines DU145 and PC3, derived from brain and bone metastasis respectively. Of note, DU145 cell lines have basal ERK activation from paracrine/autocrine factors that is not demonstrated in other cell lines. Karyotypes have been described for these lines and more recently for a variety of the other cells (...truncated)