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.

Figure 1
figure 1

Schematic representation of MAP kinse Signal transduction Pathways.

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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 lines available [5]. Studies of kinase activation in normal prostate tissue cell lines are remarkably absent from the literature.

The most well studied ligands/mitogens in prostatic cells are epidermal-derived growth factor (EGF), transforming growth factor (TGF)-α, and insulin-like growth factor (IGF). The mechanism of action of these proteins is well described in many reviews [6–8]. Generally, the ligands interact with a membrane receptor and transmit a signal to a cytosolic tyrosine kinase. EGF and TGF-α share about 35% sequence homology and bind to the same receptor, the epidermal growth factor receptor (EGFR). The ERK module appears to be a primary signal relay as inhibition of this activation prevents cellular proliferation induced by EGF as well as numerous other mitogens, which operate by transactivating the EGF receptor [9]. There are numerous effectors of the ERK pathway in prostate cancer cells and these are described in Table 1 and 2. These stresses and agents are of considerable interest in that they are potential manipulators of this cascade.

Table 1 p42/p44 MAP kinase Activating agents in Prostatic cells
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Table 2 p42/p44 MAP kinase inactivating agents in Prostatic cells
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Androgenic manipulation has been a mainstay of prostate cancer treatment for over 60 years, but the clinically challenging cancers will grow aggressively in the absence of androgens. Of considerable interest in prostate physiology is the relationship between androgens, the androgen receptor, and the MAP kinase cascade. The effect of the potent androgen dihydrotestosterone (DHT) is still unclear as it activated ERK in one study but not in numerous others with LNCaP cells [9–11]. Regardless of the effect on ERK, the contribution of MAPK to cellular proliferation due to DHT appears to be small relative to other pathways. With the apparent poor evidence suggesting direct androgen stimulation of ERK, the focus has been redirected on Interleukin (IL) -6 and the communication links between this important cytokine and the androgen receptor.

The interaction of IL-6 with the MAPK pathways is of particular interest for this is suspected to be a major autocrine factor in the progression of hormone refractory prostate cancer. There is an excellent review of the intracellular activities initiated by IL-6 [12]. IL-6 appears to be able to transactivate the androgen receptor in the absence of androgens at the N-terminal domain as well as increase the mRNA for the androgen receptor. Activation of androgen receptor by IL-6 involves the ERK pathway among others [13, 14]. ERK also appears to be involved in the phosphorylation of steroid receptor co-activator (SRC) -1, which binds to the androgen receptor [15]. LNCaP cells are also sensitive to IL-6 as an interesting study demonstrated that IL-6 exposed tumors injected into nude mice demonstrated an abrogation of proteins involved in cell cycle control. Inhibition with PD98059 was able to retard the cancer growth of these IL-6 exposed cells [16]. Our preliminary studies demonstrate that IL-6 expression by PC3, a line of hormone refractory prostate cancer cells is in part regulated by ERK signal transduction pathway (Koul et al in press]

EGF is extremely important in the study of cancer. Medications that interact with this receptor are regularly used in breast malignancies and they are being examined in many other tumor types. Interference with the EGFR either through prevention of ligand binding, disruption of surface expression, or prohibition of cytosolic protein interaction can inhibit ERK activation. Multiple studies have demonstrated interaction with EGFR by one of the aforementioned means can affect prostate cancer cell growth and invasion in PC3 and DU145 cells [17]. Tyrphostin AG825 and ZM252868 are two promising molecules that act in this fashion [18, 19]. G protein coupled receptors appeared to be very important in communicating with the EGF receptor in prostate physiology [20]. G proteins can transactivate the EGFR through a variety of means, which include cytosolic protein activation and metallomatrix protein pro-ligand cleavage. Numerous physiologic molecules normally activate this pathway including lysophosphatidic acid, bombesin, adenosine triphosphate (ATP), and 5-HETE [21–26]. A number of other metabolites appear to operate specifically via the metallomatrix protein pathway and these pathways can be inhibited with methyl selenium molecules [27].

Protein signaling

Numerous cytosolic proteins are involved in the intracellular events leading to ERK activation. Among these important molecules are ras, PTEN, ID-1, DOC-2/DAB2, Protein kinase C (PKC) epsilon and some of the integrin subtypes [28–32]. One of the intracellular proteins that transmit signals from the EGF receptor to the modular MAPK pathway is ras. Isoprenylation allows ras to approach the membrane, a requirement for interaction with the EGFR. This chemical reaction is facilitated by HMG-COA reductase and the statin-family of drugs and phenyl acetate can inhibit this process [33, 34].

The first part of the modular MAPK cascade resulting in ERK activation is the Raf molecule, which includes three isoforms, Raf-1, RafA, and RafB. These molecules have not been extensively studied with regards to prostate cancer. One interesting study used the LNCaP cell line transfected with a constitutively active form of Raf-1, which increased ERK activity and decreased plating and cloning efficiency [35]. This observation is contrary to other studies by suggesting that ERK activation may have tumor suppressor effects or perhaps chronic high level activation may have different responses. Raf kinase inhibitor protein (RKIP) is a protein that inhibits activation of MEK/ERK and appears to be a metastasis suppressor gene. Fu et al investigated clinical samples of local and metastatic prostate tissue and demonstrated immunohistochemical presence of RKIP was inversely related to histological grade. Additionally, no RKIP antigen was found in metastatic deposits. These investigators also demonstrated no effect of this protein on tumor growth, but in vitro and in vivo evidence of decreased metastasis [36]. These results support results from our lab that show inhibition of p42/p44 MAP kinase affects in vitro clonogenic potential in PC3 cells. Taken together these results suggest that inhibition of this pathway may be effective in preventing metastatic deposits, but not gross tumor growth.

Results of ERK activation

Immediately downstream of ERK, numerous proteins are activated that generally contribute to invasive potential, cell proliferation/differentiation, or survival in adverse environments. The continuation of vascular endothelial growth factor (VEGF) secretion despite cell contact appears to be regulated by ERK in LNCaP cell lines with inactivated focal adhesion kinases (FAK) via a ras-independent pathway [37]. Peroxisome proliferators-activated receptor (PPAR) Gamma appears to be an important element in regulation of proliferation and differentiation of PC3 cells. This protein is phosphorylated (inactivated) by ERK activation, thus unshackling cell growth from this control [38]. Prostate specific antigen (PSA) promotion is an ERK sensitive phenomenon in androgen independent conditions and this may explain the continuing rise in PSA in hormone refractory prostate cancer [39]. A study using PC3 cells showed that prostaglandin E2 was able to promote cell survival in oxygen poor environments by increasing hypoxia inducible factor-1α (HIF-1alpha) protein levels via a pathway inhibited by PD98059 [40]. Another study examined fibroblast-derived growth factor (FGF)-1 stimulation in LNCaP cells and this stimulation resulted in an increase in promatrilysin via ERK/STAT3 pathways [41]. This enzyme is associated with increased prostate cell invasion. Radiation exposed DU145 cells had increased production of DNA repair proteins, XRCC1 and ERCC1 by ERK related mechanisms [42]. Additionally, ERK may be involved in the expression of integrins as UO126 was able to inhibit binding to the promoter region of the alpha 6-integrin gene in only PC3 cells [43]. Androgen-sensitive LNCaP cells grown in an androgen deprived environment can develop neuroendocrine phenotypes in certain clones. ERK is constitutively activated in these cells via an elevated level of receptor-type protein-tyrosine phosphatase alpha. Inhibition of ERK with PD98059 prevents neuroendocrine differentiation and the increased level of neuron-specific enolase [44].

The effect of phospho-ERK on prostate cancer cells can either be one of reducing apoptosis or more commonly one of induction of cellular proliferation. Certainly, the relative activation of the ERK isoforms can have variable cellular effects, but this has not been evaluated in detail in prostate cancer. A few studies have demonstrated ERK dependent apoptosis in prostate cancer cells. Resveratrol in DU145 cells and phenylethyl isothiocyanate in PC3 cells both produce rapid phosphorylation of ERK and cause apoptosis [45, 46]. Other MAPK pathways do not appear necessary for this apoptotic event even though they may be activated. A few other studies view more indirect evidence that ERK activation can inhibit proliferation or other similar effects. In particular, vitamin D is able to activate ERK and also has inhibitory effects on cellular proliferation, but a causal relationship was not established [47]. Also, bryostatin 1 was able to induce apoptosis and Raf1/ERK activation in LNCaP cells that over express PKCα [48].

There is a substantial body of evidence supporting ERK and its effects on survival and proliferation. Both 13-(S)-HODE and 5-HETE cause PC3 cells to grow most likely by the ERK pathway [26, 38]. Also, inhibition of the ERK pathway has resulted in either decreased survival or increased apoptosis in cancer cell lines. In particular, 4-HPR in several studies documented apoptotic effects in multiple prostate cancer cell lines and these effects were increased with the inhibition of the ERK pathway using PD98059 [49, 50]. This suggests that under situations of cellular distress ERK attempts to rescue the cell from death. Numerous other micronutrients have shown cell growth inhibition primarily through negative regulation of the ERK pathway [51]. MEK1/2 inhibitors potentiate apoptosis caused by Tyrphostin AG825 and a check point abrogator UCN-01 in breast and prostate cancer cells [18, 52]. Also, ERK inhibition is able to increase radiation induced apoptosis in DU145 cells [53–55].

There is a growing body of evidence that identify ERK as an enzyme responsible for increased invasive and metastatic potential in prostate cancer. Our studies in PC3 cells demonstrate that ERK signal transduction pathway plays only a minor role in growth and proliferation of these cells, but is essential for clonogenic activity, cell migration and invasion [Koul S et al in preparation]. Our studies demonstrate that ERK signal transduction does not appear to play a role in cell growth, but is essential for new colony formation. This raises interesting aspects in modulation for oncologic control. Clearly, invasion and metastasis are the elements of tumors that make them malignant and the cause of patient suffering. However, ERK inhibition may not affect already developed metastatic sites. This might lend to early use of inhibitors or modulators of this pathway while disease burden is still low and/or possibly as prevention of tumor metastasis.

With such a large body of evidence supporting a role for ERK MAP kinase signal transduction pathway in promoting tumorigenesis in prostate cancer, we recognize that p42 / p44 MAP kinase signal transduction pathway may serve as a novel target for the treatment of prostate cancer.

C-JunN-terminal kinase (JNK) and the prostate

Expression and activation of JNK in tissue

The presence of active JNK in normal tissues from prostatectomy specimens is somewhat controversial, even in the same research groups [1, 2]. Most studies show that JNK expression or activation is increased in neoplastic cells [3]. Additionally, JNK activity appears to be inversely related to MKP-1 expression. An interesting sidebar to the use of transgenic adenocarcinoma of mouse prostate (TRAMP) mice by Uzgare et al showed that JNK expression can increase in poorly differentiated tumors without an apparent increase in activation. JNK is generally activated by cellular stress, however, numerous molecules are able to phosphorylate the enzyme [Table 3]. 2-methoxyestradiol (ME), an endogenous metabolite of estradiol, can synergize with taxol to increase JNK activation and enhance the apoptotic effect of this chemotherapeutic agent [56]. N-(4-hydroxyphenyl)retinamide (4-HPR) is a synthetic analog of all-trans retinoic acid and has shown some promise in localized and preventative breast cancer treatment. Poorly differentiated androgen-insensitive PC3 cells seem somewhat resistant to 4-HPR induced JNK phosphorylation, while androgen-sensitive LNCaP cells appear to be quite sensitive correlating with clinical behavior in breast cancer studies [57, 58]. Numerous other agents have been studied regarding JNK activation in prostate cancer cell lines and these include the following: Ghosh et al showed that inhibition of arachidonate 5-lipoxygenase (an enzyme that converts arachidonic acid to 5-HETE) caused rapid depletion of 5-HETE and activation of JNK, which triggered apoptosis in LNCaP and PC3 cells [59]. This suggests 5-HETE can be a critical cell cycle regulator as it activates ERK when abundant. The unique ability to activate JNK might not only come from antioxidants. Reactive oxygen species, in of themselves, can increase JNK in a study with multi-cellular prostate cancer spheroids [60]. The phorbol esters are used widely to experimentally promote tumor growth and are well known for activation of PKC. Thapsigargin is a potent inhibitor of the sarcoplamsic/endoplasmic reticulum calcium ATPase (SERCA) pump, which results in rapid increase in intracellular calcium ion.

Table 3 JNK stimulating agents in prostatic cells
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Protein signaling

While JNK appears to be involved in the cross talk between many pathways there is some research into receptors that may activate JNK. In particular, the TNF-related apoptosis inducing ligand (TRAIL) receptor can activate JNK, although this effect is not necessary for apoptosis caused by this receptor suggesting other pathways are activated [61, 62]. Certain proteins in the cell can play a roll in activating the JNK modular pathway. Prostate apoptosis response (PAR) – 4 appears to supplement JNK activity as loss of this protein caused hyperactivation of NF-kappaB and impairment of JNK and p38 [63]. In DU145 cells normally deficient of the Retinoblastoma (Rb) gene, reactivation of this gene is required for gamma irradiation induced JNK phosphorylation. Additionally, this study showed that mutant jun blocked radiation induced apoptosis [64]. Fas also plays a role in JNK activation, as well as STE20-like kinase and Janus kinase/signal transducer and activator of transcription (JAK/STAT) [12, 65, 66]. Immediately upstream is from JNK is MKK 4 and 7 which have not been studied in great detail with regard to prostate cancer. However, one study showed that MKK 4 acts as one of seven genes that are metastasis suppressers without suppressing tumor growth [67]. A number of proteins negatively regulate JNK. As mentioned previously, arachidonate 5-lipoxygenase which converts arachidonic acid to 5-HETE provides a substrate that appears to prevent JNK activation [59]. Additionally, NF-kappaB activation is able to prevent JNK phosphorylation caused by 4-HPR [49]. MAPK phosphatases have an important role in the regulation of kinase activation. Phenylethyl isothiocyanate (PEITC) increases JNK activity through the inactivation of phosphatases (M3/6) in LNCaP cells [68]. Another study showed that over expression of MKP-1 and DU145 cells blocked the activation of JNK [69]. JNK is able to activate numerous functions in the prostate cancer cell, which include both transcription factors and functional proteins. The most well known substrate for JNK is c-jun and JNK activation is synonymous with c-jun phosphorylation. JNK is able to activate the transcription factor AP1 [70]. JNK when activated can phosphorylate serine 62 on Bcl-xL, which effectively prevents this protein's anti-apoptotic effects [56]. JNK is also able to activate numerous different caspases including 3, 8, and 9, as well as prevent nucleosome formation [59, 71]. The specific activity of the different isoforms is still unknown. As lab techniques improve, undoubtedly we will have better answers. An interesting study that examined the role of JNK2 used serial analysis of gene expression (SAGE) in PC3 cells. These authors found that genes involved in DNA repair, mRNA turnover, and drug resistance were down regulated by JNK2 inactivation [72]. This suggests a role for JNK2 in cell saving. Also multiple MAPKs including JNK appear to play a role in the upregulation of the urokinase-like plasminogen activator (U-PA) promoter in PC 3 cells [73]. Regarding gross cellular function in the cell, authors have shown that activation of JNK regulates the cytoskeleton; prevention of nucleosome formation and mitochondrial dysfunction appear to also be major events following JNK activation [59, 66, 69]. JNK appears to be overwhelmingly involved in apoptotic pathways shown by multiple studies using a variety of molecules, protein and hormones to activate JNK. JNK activation has been shown to be a crucial step in the apoptosis induced by nonsteroidal anti-inflammatory drugs in human colon cancer cells [74]. Hypoxia appears to be another condition in which JNK is phosphorylated. This was shown in male rats that were castrated and subsequently had the environment of the ventral prostate gland examined [75].

Results of JNK activation

JNK activation is not a necessity for apoptosis as demonstrated in multiple studies using inhibitors or dominant negative cell lines. Despite overwhelming studies suggesting JNK activation and apoptosis, several well-performed studies suggest that JNK inactivation is beneficial. Different roles for JNK1 and JNK2 are of interest and poorly understood. As mentioned previously, JNK2 inactivation prevented the up regulation of genes involved in DNA repair, mRNA turnover and drug resistance [72]. Other studies using anti-sense forms of JNK have revealed some interesting findings. One study has suggested that JNK is more active in growth and proliferation [76]. These authors exposed human prostate cancer lines to anti-sense JNK1 and JNK2 and found that anti-sense JNK1 inhibited growth and anti-sense JNK2 inhibited proliferation. This study suggests that JNK is a potential target for prostate cancer growth. Another study reviewed the methods for sensitizing prostate cancer cells to cisplatin, by expression of p53 and anti-sense JNK [77].

p38 MAP kinase MAP kinase (p38) and the prostate

In non-cancerous human prostate tissue p38 MAP kinase protein is present in the basal cells and epithelial cells of the prostate gland, but one study has shown it to be absent in the epithelial layer [2]. While likely present it is not normally activated in epithelial tissue samples that have been studied, but has stronger activity in the prostatic stroma similar to ERK. However, epithelial p38 MAP kinase can become active in situations of neoplasia and benign hypertrophy of the prostate gland [3]. One study using TRAMP mice suggested that the strong epithelial p38 MAP kinase activation present in intraepithelial neoplasia and well-differentiated tumors but might be lost in poorly differentiated tumors [78]. Similar to JNK, p38 MAP kinase is a kinase primarily activated by external stresses. Table 4 describes a number of other activators. Many growth and endocrine factors are able to activate p38 MAP kinase including FGF-1 and -2, keratinocyte-derived growth factor (KGF), IL-6, heparin binding epidermal growth factor (HB-EGF), ATP, vitamin D, and Neu differentiation factor (NDF) [13, 25, 47, 79–81]. This activation has been demonstrated in both DU145 and LNCaP cells. However, PC3 cells are conspicuously absent from studies involving p38 MAP kinase activation, at least in regards to the response to growth and endocrine factors. Response of p38 MAP kinase to these various hormones can range in time from several minutes to several hours, which suggests indirect inducible activation of this MAPK.

Table 4 p38 MAP kinase activating agents in prostatic cells
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Intracellular signaling prior to the p38 MAP kinase module appears to be complex and incompletely described. Protein kinase C is able to activate p38 MAP kinase, although perhaps indirectly [82]. PAR4 loss causes impairment of p38 MAP kinase phosphorylation[63]. The JAK/STAT family of proteins also appears to be able to activate p38 MAP kinase [12]. The particular roles of the immediate upstream activator of p38 MAP kinase, MAPKK 3/6, have not been studied extensively in the prostate literature. The immediate downstream proteins and transcription factors of p38 MAP kinase are still in the process of being defined, and have not been studied in prostate. p38 MAP kinase is well known to activate the transcription factor NF-Kappa B [83]. p38 MAP kinase also appears to have some role in activating caspases [84]. p38 is also able to increase the expression of certain proteins including chromium induced HIF-1α expression, up regulation of the U-PA promoter in PC3 cells, and PSA induced by IL-6 in LNCaP cells [73, 85, 86]. P38 inhibition was able to decrease the activation of actin stress fibers in DU145 cells [79, 87]. This appears to be largely a role induced by growth factors. Another study demonstrated neuroendocrine differentiation in LNCaP cells via a p38 MAP kinase dependent mechanism [80]. Some authors have postulated the determination of the p-ERK to p-p38 MAP kinase ratio might be able to predict the in vivo behavior of cancer, including the prostate [88]. Cellular death appears to be the overwhelming effect of cells with active p38 MAP kinase. Again as in the case with other signals, p38 MAP kinase is not requisite for cellular apoptosis and clearly the balance of p38 MAP kinase activation versus other signals probably determines cellular outcome. Our studies demonstrated that inhibition of p38 MAP kinase pathway resulted in inhibition of the DNA synthesis and growth and proliferation of PC3 cells. [Koul et al In preparation]. Additional studies in our laboratory are currently underway in to further evaluate function of p38 MAP kinase signaling pathway in other prostate cancer cell lines.

Conclusions and future directions

MAPK signal transduction pathways seem to play diverse role in prostate physiology. Significant differences have been observed in the activation pattern of all three major MAPK families (ERK, JNK and p38 MAPK) in prostate epithelial and stromal cells and under normal and pathophysiological conditions. Modulation of these MAP kinase pathways has also been demonstrated in various prostate cancer cell lines by growth factors, cytokines and variety of agents that modulate growth and apoptosis of these cells. However, structure and function of MAP kinase signal transduction pathways have not been defined in sufficient detail in prostate gland under normal conditions and under the pathologic conditions like benign hyperplasia and prostate cancer. Moreover, prostate is a heterogeneous gland, comprising of several cell types each cell type regulating the function of the other cell type by para-crine mechanisms, it is important to understand the role played by MAP kinase signal transduction pathways in mediating communication between various neighboring cell types in the prostate. Despite these limitations, ample circumstantial evidence suggests an important role for MAP kinase signal transduction pathways in prostate physiology and pathophysiology. Thus additional studies are warranted to study the structure of MAP kinase pathways in prostate epithelial cells under normal and pathophysiological conditions of BPH and PCa. In addition, we know a divergent array of signaling cascades can serve as activating elements upstream of the core MAPK modules [Fig 1]. Identification of the signaling cascades that are selectively activated in normal prostate and in hormone responsive and hormone refractory prostate cancer cells is critical in identification of selective targets and development of new and rational therapies for treatment of prostate cancer.