G Proteins in Cancer: The Prostate Cancer Paradigm

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Science's STKE  20 Jan 2004:
Vol. 2004, Issue 216, pp. re2
DOI: 10.1126/stke.2162004re2


Signal transduction research investigating mechanisms of androgen-independent prostate cancer cell proliferation has historically focused on the role of androgen and peptide growth factor receptors. More recent work has raised the idea that intracellular signaling mechanisms triggered by extracellular hormonal factors acting through heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) can also mediate and sustain this pathologic process. Prostate cancer patients with advanced disease express elevated levels of GPCRs and GPCR ligands, suggesting that the GPCR system is activated in the cancerous gland and may contribute to tumor growth. Importantly, inhibition of G protein signaling attenuates prostate cancer cell growth in animal models. The nature of intracellular signaling pathways mediating mitogenic effects of GPCRs in prostate cancer is poorly defined, although the G protein-dependent activation of the Ras-to-mitogen-activated protein kinase pathway has emerged as a critical regulatory event. Activated GPCRs may also exert their mitogenic effects in the prostate by activating the androgen receptor.


Prostate cancer is the most-diagnosed malignant growth in men and is the second-leading cause of male cancer deaths in the majority of Western countries. In 2003, an estimated 221,000 men were diagnosed with prostate cancer, and 28,900 died from the disease in the USA (1). Risk factors for prostate cancer are many and span the spectrum from specific gene rearrangements to lifestyle matters, such as diet (2, 3). The cancerous gland usually contains multiple independent and genetically distinct lesions, demonstrating heterogeneity of the disease (4, 5).

Patients with cancer confined to the prostate gland have several treatment options, including watchful waiting, surgery, and radiation. However, because pathologic growth of the prostate is controlled largely by steroid androgens [mainly dihydrotestosterone (DHT)], treatment of locally advanced or metastatic disease relies heavily on hormonal therapies that target the androgen receptor (AR). These therapies include (i) androgen ablation by physical or chemical castration of the patient to reduce levels of circulating androgens, (ii) treatment with AR antagonists to disrupt receptor activation, or (iii) a combination of both (68). A major limitation of hormonal therapy, however, is that it offers only temporary relief; the cancer eventually reappears as an androgen-independent (AI) lesion characterized by aggressive growth and invasion of distal organs, predominantly the bone (9). Despite decades of intense laboratory and clinical investigations, there is no cure to date for metastatic or AI prostate cancer.

Factors involved in the transition of the prostate tumor from androgen-dependent (AD) to AI are not well established and present a major hurdle to improving disease outcome. Two possibilities may explain the appearance of AI prostate cancer (6, 9, 10). One explanation is that AI cells may coexist with AD cancer even at the initial stages of the disease. Hormonal therapies target the AD lesions and, as a result, provide a selective growth advantage (clonal expansion) to AI cancer cells. An alternative explanation is that AI disease may emerge directly from AD cancer cells as a result of genetic alterations (adaptation) induced by the hormonal therapy, which allow the cancer cells to survive and grow in the androgen-depleted microenvironment. Whether it is clonal expansion or adaptation, development of AI prostate cancer shows clearly that factors other than, or together with, androgen must exist to provide survival and growth instructions to the AI cells.

Basic and clinical research results demonstrate that, in AI neoplasms, the AR is activated despite the continued presence of the hormonal therapies and is involved in the transition of the prostate cancer from AD to AI (11). First, AR is overexpressed in up to one-third of AI prostate carcinomas, suggesting a compensatory mechanism by which the AR adjusts its physiologic rheostat to respond to lower serum levels of androgens (9, 12). Second, AI lesions exhibit frequent mutations in the AR, which could allow it to be activated by androgens other than DHT, or even anti-androgens (9, 13). The frequency of AR mutations in localized prostate cancer is low, suggesting that AR mutations may not be the primary cause of tumor initiation (14). Third, AR can be transactivated by factors other than androgens, including cytokines (15) and peptide growth factors (9, 12, 16), which exert their effects on target cells by activating their cognate plasma membrane-anchored receptors (Fig. 1).

Fig. 1.

Activation of androgen receptor by androgen (A) and other extracellular stimuli (B) in prostate cancer cells. Binding of androgens such as dihydrotestosterone (DHT) causes activation, but not phosphorylation, of AR. FSK, forskolin; AC, adenylyl cyclase; PMA, phorbol myristate acetate; PKC, protein kinase C.

AR Activation

Studies of the initiation and progression of prostate cancer have centered on AR signaling. The AR is a ligand-activated transcription factor that mediates biological effects of male sex steroids in the target cell by activating transcription of androgen-regulated genes (17). Upon ligand binding, AR associates with coactivators and acquires the ability to dimerize and bind specific DNA sequences, termed androgen response elements (AREs), in the promoter and enhancer regions of androgen-regulated genes to activate their transcription.

The AR also undergoes ligand-independent transactivation in response to stimulation of specific cell surface receptors. In androgen-insensitive prostate cancer DU145 cells ectopically expressing human AR, stimulation of endogenous insulin-like growth factor 1 (IGF-1) receptors activates transcription of ARE-regulated reporter genes (18). Similarly, in androgen-sensitive prostate cancer LNCaP cells, stimulation with epidermal growth factor (EGF), interleukin-6 (IL-6), or IGF-1 promotes secretion of prostate-specific antigen (PSA) expressed from an ARE-containing promoter, in the absence of exogenously added androgen (19).

Overexpression of EGF receptor (EGFR) family member HER2 (also known as neu) in androgen-sensitive prostate cancer LAPC-4 cells leads to AR activation and subsequent AI cell proliferation (20). Activated HER2 stimulates the activity of the AR and synergizes with low concentrations of androgen to further activate the AR. In vitro, the HER2-mediated induction of PSA expression requires functional ARs, and in mice, transition of the AD LAPC-4 xenografts to AI tumors is associated with increased expression of HER2 (20).

The activation of AR is also controlled by accessory proteins, including the steroid receptor coactivator 1 (SRC-1), transcriptional intermediary factor 2 (TIF2), and the related SRC-3 variants AIB1 and RAC-3 (21, 22). These coactivators increase AR transactivation in the presence of androgen (23). Recently, the Wilson group reported that EGF increased AR activity through increased phosphorylation of TIF2. The EGF-induced increase in TIF2 phosphorylation was mediated by extracellular signal-regulated kinase 1 and 2 (ERKs) (24). These results contrast with those reported by Chang and colleagues, who demonstrated existence of a HER2 → ERK → AR signaling pathway in cultured LNCaP cells (25). ERK was shown to directly phosphorylate AR in vitro, and inhibition of ERK activity attenuated the HER2-mediated activation of AR (25).

GPCRs and Prostate Cancer

Growth of prostate cancer is sustained by release of circulating and locally produced factors acting through cellular receptors that can switch the quiescent prostate cells to an activated state, leading to cellular proliferation. Increasing evidence supports the involvement of G protein-coupled receptors (GPCRs) (26) in neoplastic transformation of the prostate (12, 27) (Table 1). First, the cancerous prostate contains elevated levels of enzymes that control expression of GPCR ligands. An example is human kallikrein 2 (28), which is expressed strictly in epithelial prostate cells and possesses kininogenase activity to produce kinins (29). Kinins are ligands for the GPCRs bradykinin 1 and 2 and are involved in various physiologic and pathophysiologic responses, including pain, vascular permeability, and cell division (30, 31). Second, prostate cancer cells produce increased amounts of GPCR ligands, including follicle-stimulating hormone (FSH) (32), endothelin 1 (ET-1) (33, 34), and lysophosphatidic acid (LPA) (35, 36). Third, malignant prostate specimens express higher levels of GPCRs, including the orphan prostate-specific GPCR (37), bradykinin 1 receptor (38), FSH receptor (39) and endothelin 1A receptor (ET1AR) (34, 40), compared to the levels in benign prostate tissue. Thus, the malignant prostate expresses increased levels of GPCRs and their ligands, which suggests that the GPCR system may always be "on" and, therefore, may contribute to initiation or progression of the disease. Indeed, clinical trials targeting the ET1AR are currently under way for the treatment of prostate cancer patients (41). Encouraging preliminary results show that inhibition of ET1AR signaling, using the receptor antagonist atrasentan, significantly prolonged time to progression, defined as the development of new lesions in the bone or soft tissue, in treated prostate cancer patients, compared with the placebo group (42).

Classical GPCR Signaling

Receptors coupled to G proteins account for roughly 1% of the human genome and form the largest known family of cell surface receptors (26, 43). GPCRs are composed of distinctive seven-transmembrane α-helical domains interconnected with extracellular and intracellular loops. The GPCRs mediate cellular responses to a diverse array of signaling molecules, including neurotransmitters, phospholipids, and peptide and glycopeptide hormones, and are common targets for clinically used drugs.

The basic signaling unit of a GPCR system contains three parts: receptor, trimeric αβγ G protein, and effector (Fig. 2). The binding of ligand to a GPCR promotes interaction with G proteins, resulting in the exchange of guanosine diphosphate (GDP) for guanosine triphosphate (GTP) on the Gα subunit, and subsequent dissociation of the Gα-GTP from the Gβγ subunits. The Gα-GTP and Gβγ subunits independently activate downstream effectors to generate specific cellular responses (44, 45).

Fig. 2.

Activation cycle of heterotrimeric G proteins. An agonist-bound receptor catalytically activates the G protein, leading to exchange of GDP for GTP on the α subunit. Gα-GTP dissociates from the Gβγ subunit, and each activates specific effector to elicit the cellular response. Hydrolysis of GTP to GDP promotes reassociation of the Gα-GDP with Gβγ subunit to produce the inactive heterotrimeric complex. H, hormone.

G proteins are typically divided into four groups on the basis of sequence homology of the Gα subunit (Table 2). In mammals, Gαs proteins generally stimulate adenylyl cyclases (ACs), whereas Gαi proteins, which are sensitive to pertussis toxin, are often inhibitors of ACs (46). Activated ACs produce adenosine 3′,5′-monophosphate (cAMP), which activates at least three known effectors: protein kinase A (PKA), guanine nucleotide exchange factor activated by cAMP (Epac), and cyclic nucleotide-gated channels (4547). Activated Epac activates the small guanosine triphosphatase (GTPase) Rap proteins, which are involved in cell growth and motility (47). Gαq proteins regulate the activity of phosphatidylinositol-specific phospholipases to generate lipid second messengers, which, in turn, elevate the levels of intracellular Ca2+ and cause activation of protein kinase C (PKC) (44, 45). Other G protein family members include Gα12/13, which regulate the GTPase Rho (44, 45). Gβγ subunits also regulate the activity of several effector molecules, including ACs and protein tyrosine kinases (48).

Fig. 3.

GPCR-regulated activation of ERK by second messenger-dependent pathways. Gαs-GTP activates adenylyl cyclase (AC) to produce cAMP, which leads to activation of ERK. Gαq promotes the release of Ca2+ ions from intracellular stores, which promote activation of ERK. See text for details.

Fig. 4.

GPCR-mediated transactivation of EGFR. Stimulated GPCR induces activation of matrix metalloproteinase (MMP) by Gβγ subunits. Activated MMP proteolytically cleaves plasma membrane-anchored EGF-like propeptides to produce soluble and biologically active hormones. The EGFR ligands bind their cognate receptors in an autocrine or paracrine manner, leading to the activation of the ERK pathway.

Fig. 5.

Activation of AR by G protein-dependent mechanisms. ARA, androgen receptor activator. See text for details.

Table 1.

Partial list of GPCR ligands that promote mitogenic signaling in prostate cancer cells.

Table 2.

Trimeric G proteins and their effectors. olf, olfactory; t, transducin; g, gustducin; GRK, G protein-coupled receptor kinase; PI3K, phosphatidylinositol 3-kinase.

In the classical paradigm, GPCR-mediated signal transduction involves the agonist-dependent interaction of GPCRs with G proteins at the plasma membrane, and the subsequent generation, by membrane localized effectors, of soluble second messengers or ion currents (Fig. 2). Rapid termination of GPCR signaling is brought about by phosphorylation of agonist-occupied receptors by members of the G protein-coupled receptor kinase (GRK) family, and subsequent binding of β-arrestin proteins (26, 49). Binding of β-arrestin proteins to receptors uncouples the receptor from its cognate G protein, resulting in a decreased responsiveness of the signaling system to agonist, termed "desensitization" (50). The β-arrestins also initiate the process of receptor sequestration by targeting it to clathrin-coated pits for internalization (51). Sequestered receptors are either dephosphorylated and recycled to the cell surface, termed "resensitization," or targeted for degradation.

Mitogenic GPCR Signaling

Although proliferative signaling has generally been attributed to peptide growth factor receptors that possess ligand-regulated protein tyrosine kinase activity (52, 53), growing evidence suggests that GPCRs, which lack intrinsic kinase activity, also mediate mitogenic responses to various substances and participate in the regulation of pathologic cellular growth (26, 27, 44). For example, several oncogenes encoding mutated forms of GPCRs, their associated G proteins, or proteins involved in their signaling pathways have been identified. Activating mutations of the thyrotropin (54) and luteinizing hormone (55) receptors have been detected in adenoma of the thyroid and hyperplastic Leydig's cells, respectively. Sequences encoding functional GPCRs have been identified in the genomes of transforming viruses, including herpesvirus saimiri (56) and Kaposi’s sarcoma-associated herpesvirus (57). The latter encodes a constitutively active and transforming GPCR and was recently demonstrated to cause cancer in animal model systems (58). Further, the transforming oncogenes gsp (59), gip2 (60), and gep (61, 62) encode activating mutants of Gαs, Gαi2, and Gα12, respectively.

In tissue culture systems, stimulation of prostate (and many other) cell types with GPCR ligands such as acetylcholine (63), angiotensin (64, 65), bombesin (64, 66), bradykinin (38, 67, 68), ET-1 (33, 34), FSH (32), isoproterenol (69), LPA (7072), neurotensin (73), prostaglandin (74), or thrombin (75) elicits mitogenic responses. Thus, it is now well accepted that the GPCR and G protein systems convey signals that control cell growth in several human diseases, including prostate hypertrophy. Often, these effects are mediated by specific intracellular signaling networks, especially the ERKs, which may play an important role in prostate tumorigenesis (76, 77).

ERK in Prostate Cancer

The ERK family is composed of evolutionarily conserved serine-threonine kinases that transmit signals regulating cell growth and survival. Signal relay that activates ERK proceeds through a tripartite kinase module consisting of Raf → MAPK-ERK kinase (MEK) → ERK (78). Once activated, ERKs may stay in the cytoplasm to phosphorylate various proteins or may translocate to the nucleus to activate transcription factors involved in DNA synthesis and cell division. Human prostate biopsies have increased levels of activated ERKs in malignant tissues compared to those in benign specimens. Further, activated ERKs are most prevalent in advanced-stage prostate tumors and in tumors that have recurred after androgen-ablative therapy (76, 77). Collectively, these findings suggest that ERKs play critical role in prostate tumorigenesis.

In tissue culture, serum-regulated prostate cell growth is mediated by ERK, and inhibition of ERK activation blocks cell proliferation. This serum-regulated ERK activation and subsequent cell growth is dependent on G proteins. For example, inhibition of Gαi signaling by pertussis toxin attenuates ERK activation and growth of AI prostate cancer PC3 cells (70). The nature of the intracellular signaling pathways mediating ERK activation by the GPCRs and their associated G proteins is complex and varies substantially among receptors and cell types. GPCR-mediated activation of the ERK cascade can be achieved through second messenger-dependent pathways (Fig. 3), such as cAMP → PKA-dependent phosphorylation of the GTPase Rap-1 (79), the Ca2+ → PKC-dependent activation of Raf (44, 80), and the Ca2+-dependent activation of focal adhesion kinase Pyk2 (81, 82). In AI prostate cancer cells, however, classical second messenger-dependent mechanisms have proven inadequate to explain the GPCR-regulated activation of ERK and subsequent prostate cancer cell proliferation (12, 27). The emerging picture is that agonist-stimulated GPCRs activate ERK through transactivation of receptor tyrosine kinases.

Cross Talk Between GPCR and EGFR in Prostate Cancer

The cell surface is decorated with many receptors that are simultaneously bombarded with extracellular stimuli and collectively control the cellular response. Exposure of prostate cancer PC3 cells to LPA elicits a dramatic reduction in the concentration of exogenous EGF required for maximal activation of the EGFR (72), suggesting existence of cooperative cross talk between the two receptor subtypes. Further, stimulation with LPA alone increases the phosphorylation of EGFR and ERK (70, 72), demonstrating that LPA "transactivates" the EGFR. Here, transactivation refers to the process by which EGFR becomes tyrosine phosphorylated in the absence of added EGF. Temporally, the LPA-induced tyrosine phosphorylation of EGFR occurs before ERK activation, suggesting that phosphorylated EGFR may be an obligatory component in the signal relay from LPA receptor to ERK in prostate cancer cells (72). Indeed, LPA-mediated activation of ERK in PC3 cells is blocked by pharmacologic inhibition of intrinsic EGFR tyrosine kinase activity (70, 72). Importantly, blockade of EGFR activation also inhibits cell division (67).

Investigations of the mechanism of EGFR transactivation by GPCRs failed initially to detect the secretion of EGF (83), suggesting that EGFR transactivation occurred exclusively through an "inside-out" mechanism. Indeed, in the case of the β2 adrenergic receptor (β2AR) in fibroblasts, stimulation with isoproterenol triggered redistribution of the nonreceptor tyrosine kinase c-Src from intracellular lipid vesicles to the plasma membrane, where it formed a complex with the β2AR using β-arrestin as the adaptor protein (84). Subsequent studies demonstrated the existence of an isoproterenol-dependent β2AR-EGFR complex that contained c-Src and β-arrestin (85). Selective inhibition of c-Src activity prevented both agonist-induced formation of the complex and activation of ERK, demonstrating that c-Src activity occurred and was necessary for EGFR activation. On the basis of these results, it was proposed that β-arrestin brings activated c-Src into the vicinity of EGFR, resulting in phosphorylation and activation of the receptor by c-Src (84, 85).

In PC3 cells, stimulation with LPA induces the tyrosine phosphorylation of EGFR on Tyr845 (72), a known c-Src phosphorylation site (86), presumably leading to activation of the intrinsic tyrosine kinase activity of EGFR and autophosphorylation. Tyrosine-phosphorylated EGFR then presents docking sites for recruitment of proteins, including Grb2 and its associated Ras guanine exchange factor son of sevenless (SOS), to the plasma membrane. Recruitment of Grb2-SOS facilitates the exchange of GDP for GTP on Ras, leading to recruitment and activation of Raf. Subsequent signal transduction involves the sequential phosphorylation of MEK and ERK.

In prostate cancer cells, evidence also supports the existence of an "inside-out-inside" mechanism for EGFR transactivation (Fig. 4), in which EGF-like ligands are released from the cell surface in response to GPCR stimulation (27, 65, 72). Each of the known ligands for the EGFR--namely, EGF, transforming growth factor α (TGF-α), heparin bound (HB)-EGF, betacellulin, amphiregulin, and epiregulin--is synthesized as a transmembrane precursor that undergoes regulated proteolysis to produce a soluble, and biologically active, growth factor (87). In fibroblasts, transactivation of EGFR by several GPCRs, including those for thrombin, LPA, and angiotensin, is mediated primarily by the regulated release of HB-EGF (88, 89). Proteolysis of the HB-EGF precursor is mediated by members of the ADAM family of matrix metalloproteinases (MMPs) (88). In AI prostate cancer cells, stimulation with LPA promotes the MMP-regulated phosphorylation of EGFR and subsequent activation of ERK in a mechanism that is independent of HB-EGF, EGF, or TGF-α shedding (72). Consistent with these results are the observations by Ullrich and co-workers that in squamous cell carcinoma cells, stimulation with LPA induces the TNF-α converting enzyme-regulated release of amphiregulin and subsequent activation of EGFR (90). Thus, it is reasonable to propose the existence of prostate cancer cell-specific mechanisms (and intermediates) that regulate the GPCR-mediated transactivation of EGFR by ligand shedding and subsequent stimulation of cell proliferation.

Although stimulation of Gs-, Gi-, and Gq-coupled receptors induces the robust ERK activation in many cell types (including prostate), expression of activated mutants of Gαs, Gαi, or Gαq often fails to activate ERK (44, 91), suggesting involvement of Gβγ subunits. Indeed, forced expression of a Gβγ-sequestering peptide derived from the C-terminus of GRK2, GRK2ct (92), effectively inhibits LPA-stimulated ERK activation in PC3 cells (70). Thus, the signaling pathway from LPA receptor to ERK in the prostate cancer PC3 cells proceeds by a Gβγ → MMP → shedding of EGF-like peptide → EGFR → ERK pathway (Fig. 4). Expression of the GRK2ct peptide attenuates serum-induced ERK activation and PC3 cell proliferation in vitro (70), as well as PC3 tumor formation in xenograft animal models (93). These findings suggest that the majority of the mitogenic activity present in serum is mediated by factors that signal through Gβγ subunits.

What are the Gβγ effectors involved in the shedding of EGF-like peptide? Exact effectors of the Gβγ subunits remain undefined, although phosphatidylinositol 3-kinase (PI3K) and c-Src family nonreceptor tyrosine kinases may be early intermediates in the pathway (Fig. 4). Free Gβγ can directly bind the regulatory p101 subunit of PI3Kγ, leading to PI3Kγ activation (94, 95). Inhibition of PI3K activity eliminates GPCR-regulated activation of ERK in PC3 cells (70). In fibroblasts, Gβγ subunits also regulate the targeting to the plasma membrane and activation of c-Src (84). Here, the Gβγ subunits serve to recruit GRK2 to the plasma membrane, where it phosphorylates agonist-occupied GPCR, which, in turn, serves as high-affinity binding site for β-arrestin-c-Src complexes (26, 49, 84). Inhibition of c-Src activity prevents GPCR-induced ERK activation (84). It is probable that activated PI3K and c-Src regulate (directly or indirectly) the activity of plasma membrane-anchored MMP to produce EGF-like ligands that activate EGFR exactly as if it were stimulated with EGF.

From GPCRs to AR Through HER2

Cross talk between receptors of distinct classes greatly increases diversity in signal transduction (27, 87), and several lines of evidence suggest that G proteins may regulate AR function (Fig. 5). For example, cross talk between EGFR and AR (20, 24, 25), at least in animal models, appears to be important for progression of the prostate cancer to AI (20). In this particular model, activation of the EGFR HER2 was accomplished by forced overexpression. Conflicting reports exist regarding the relationship between expression levels of EGFRs and progression to AI prostate cancer in men. One study reported that expression of HER2 protein was higher in prostate tumors that were treated with androgen-ablative therapy compared to pretreatment levels, and that the incidence of HER2-positive tumors increased after androgen deprivation (96). Another study showed no correlation between HER2 expression and progression to AI disease (97). It is likely that activation state, rather than expression level of HER2, is the important factor in the transition to AI prostate cancer. In support of this conclusion are the recent findings that inhibition of HER2 signaling with neutralizing antibodies attenuates growth of xenografted breast and prostate cancer tumors that do not overexpress the receptor (98).

An alternative mechanism to overexpression of HER2 in the activation of this receptor in prostate cancer is by activated GPCRs and their associated G proteins (Fig. 3 and Fig. 4). Thus, it is possible to envision a signaling pathway in advanced prostate cancer cells (that express normal levels of HER2) that consists of GPCR → HER2 → AR.

From IGF-1 to AR Through G Proteins

Patients with advanced prostate cancer express elevated levels of circulating IGF-1, which may play a role in the development and progression of the cancer (99, 100). In transgenic mice, expression of human IGF-1 in basal epithelial cells of prostate activates IGF-1 receptor (IGF-1R) and yields spontaneous neoplastic growth in prostate epithelium (101). In vitro, IGF-1 activates AR in the absence of androgen (18). Mechanisms involved in the IGF-1-regulated AR activation and subsequent prostate cell growth are not clear, but may involve G proteins. IGF-1-stimulated synthesis of DNA is sensitive both to pertussis toxin and to microinjection of GRK2ct peptide (102). In addition, treatment with pertussis toxin attenuates the IGF-1-mediated activation of ERK in PC3 cells. Stimulation with IGF-1 induces the direct interaction between IGF-1R and Gαi, Gβγ subunits, and β-arrestin (103, 104). These interactions promote IGF-1-induced ERK activation (103, 104). Thus, it is possible that the IGF-1-mediated activation of AR and cell proliferation are mediated by G proteins in advanced prostate cancer.

From G Proteins to AR Through PKA

The AR is a phosphoprotein, and reversible phosphorylation appears to play an important role in ligand-dependent and ligand-independent AR activation (105). The Weber group identified six phosphoserine residues in AR (106), and one residue (Ser650) became phosphorylated in response to stimulation with forskolin (FSK). The diterpene FSK binds directly to ACs (107) to promote synthesis of cAMP, which activates, among other things, PKA. Two lines of evidence suggest an important role for PKA in the activation of AR. First, inhibition of PKA activity abolished the FSK-regulated transactivation of AR in prostate cancer cells (108110). Second, expression of the catalytic subunit of PKA promoted activation of ARE-regulated reporter gene (110). The best-studied cellular mechanism to activate ACs and PKA involves Gαs proteins (45). On the basis of these observations, we propose that dysregulated signaling by Gαs could control AR activation in prostate cancer cells and may contribute to progression of the disease to the AI state.

From G Proteins to AR Through Rho

Another mechanism likely to play an important role in the regulation of AR function in advanced prostate cancer involves the GTPase Rho. Rho may exert its effect on AR by (i) promoting translocation of the LIM-only transcriptional coactivator FHL2 (four and a half LIM 2) from the cell membrane to the nucleus, leading to transcriptional activation of AR-dependent genes (111), or (ii) activation of the PKC-related kinase PRK1, leading to ligand-dependent superactivation of AR-regulated genes (112). Activated PRK1 stimulates AR transcriptional activity even in the presence of the anti-androgen cyproterone acetate. The activation of Rho proteins by stimulation of GPCRs coupled to members of the Gα12/13 family (45) provides another potential link between AR activation and G proteins. Activated Gα12/13 stimulates Rho guanosine exchange factors that, in turn, activate Rho. Thus, dysregulated signaling by the Gα12/13 should activate AR through Rho, leading to progression of the disease.


The observation that prostate cancer is a heterogeneous disease arising through a variety of genetic and environmental maladaptations implies that no monotherapy is sufficient to cure this chronic disease. Indeed, although hormonal therapies targeting the AR show initial successes, the cancer often progresses to a hormone-refractory state. Recent discoveries have identified growth factor receptors (for example, EGFR, IGF-1R) as contributors to hormone-independent prostate cancer. However, clinical trials targeting the EGFR, for example, have shown limited success, and in only a subset of prostate cancer patients. These clinical results reinforce the conclusion that efficient management of the disease will likely require combination therapies aimed at multiple targets.

In this review, evidence for the possible contribution of GPCRs and G proteins to prostate tumorigenesis is described. Dysregulated expression of GPCRs and their ligands is linked to the development of prostate cancer and transition to currently incurable AI disease. The G proteins regulate prostate cancer cell proliferation in vitro and in animal models. Mechanisms involved in the G protein-dependent prostate cancer cell proliferation are under investigation and may involve commandeering the activities of tyrosine kinase receptors or stimulating ARs in the absence of androgens. Development of medicines in the forms of small molecule receptor antagonists or neutralizing antibodies that target the GPCR-G protein signaling pathways may prove, in combination with other targeted drugs, more effective for the successful treatment of men with advanced prostate cancer.


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