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Tumor Biology |
Department of Microbiology and Cancer Center, University of Virginia, Charlottesville, Virginia 22908 [T. C., R. W. C., M. J. W.]; and Vollum Institute, Oregon Health Sciences University, Portland, Oregon 97201 [P. J. S. S.]
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ABSTRACT |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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One of the signals that regulates the activation of MAPKs is cAMP, which operates by activation of PKA. Elevation of intracellular cAMP inhibits activation of MAPK and stimulation of growth in response to growth factor treatment in fibroblasts such as NIH3T3 and Rat-1 cells (9, 10, 11, 12) , smooth muscle cells (13) , and adipocytes (14) . On the other hand, in phaeochromocytoma PC12 cells, elevation of intracellular cAMP induces activation of MAPK, MAPK-dependent activation of the transcription factor Elk-1, and differentiation into a neuronal phenotype (15) .
In the classic pathway, activation of MAPK occurs by peptide growth factors that bind to a transmembrane tyrosine kinase receptor. Receptor engagement results in the activation of the small GTP-binding protein Ras that recruits a member of the Raf kinase family (Raf-1, A-Raf, or B-Raf) to the plasma membrane. At the membrane, Raf becomes activated and, in turn, phosphorylates and activates the MEKs (MEK1 and MEK2), which then activate the MAPKs ERK1 and ERK2 by phosphorylation on threonine and tyrosine (16, 17, 18) . cAMP inhibits this pathway, at least in part, by blocking the binding of Raf-1 to Ras (9) . In PC12 cells, in which cAMP activates MAPK, this occurs through PKA-induced activation of the Ras-related small G protein Rap1 (15) . The activated Rap1 is both a selective activator of B-Raf and an inhibitor of Raf-1. Thus, in PC12 cells, which express B-Raf, activation of Rap1 by cAMP results in activation of the MAPK pathway and the induction of neuronal differentiation (15) ; in cells with little or no B-Raf (e.g., fibroblasts), cAMP inhibits the MAPK cascade.
Peptide growth factors that activate the receptor tyrosine kinase 
Ras MAPK pathway are widely suspected to play an important role in the progression of prostate cancer. For example, prostate epithelium and prostate cancer cells express the EGF receptor, and as expected, EGF and TGF-
are strong mitogens for cultures of these cells (19)
. In primary prostate cancer, TGF- is produced by stroma, and the EGF receptor is located in the epithelial cells, implying a paracrine mode of interaction. Prostate cancer progression correlates with co-production of both the growth factor and the receptor by the tumor cells, suggesting that the tumors may switch to an autocrine mode in advanced disease (20)
. In addition to EGF and TGF-, other growth factors, such as insulin-like growth factor-I, IL-6, keratinocyte growth factor, and FGF are produced by prostate cancer cells (19
, 21)
.
Human prostate cells are exposed not only to peptide growth factors but also, simultaneously, to neuropeptides produced by prostatic neuroendocrine cells. Neuropeptides described in prostate cancer cells include bombesin, serotonin, thyroid-stimulating hormone-like, parathyroid hormone-like, and calcitonin-like peptides (22, 23, 24) . These neuropeptides and related agonists characteristically interact with serpentine receptors that activate heterotrimeric G proteins and elevate cellular cAMP levels. As with the growth factors, the neuropeptides have been implicated in the regulation of prostatic cell proliferation, differentiation, and movement. For example, in prostate cancer cell lines, cAMP has been shown to induce neuroendocrine differentiation (25) , and neuropeptides such as calcitonin have been shown to stimulate growth of LNCaP cells through receptor-mediated increases in cAMP and Ca2+ (26) . Furthermore, bombesin and VIP have been reported to enhance the invasiveness of LNCaP cells by stimulating adenylate cyclase (27) .
The population of neuroendocrine cells increases as prostate cancer progresses, and secretion of neuropeptides is relatively higher in cancer samples than it is in benign samples (26) . Staining of paraffin sections reveals higher indices of growth, as measured by Ki67 staining, in cells surrounding the neuroendocrine cells than elsewhere in the prostate tumor (28 , 29) . These findings raise the possibility that, as with the peptide growth factors, increased production of neuropeptides may contribute to increased prostate cancer growth and progression.
Although MAPK is central to the growth, differentiation, and movement of many cell types and undoubtedly plays a role in the responses of prostate cells to growth factors and neuropeptides, the interaction(s) between the MAPK and PKA pathways has not been investigated in human prostate cancer cells. Because these interactions can be either antagonistic or concordant, which can have substantial implications for cell behavior, it is important to elucidate the mechanisms by which "cross-talk" occurs between these pathways. We have used androgen-responsive LNCaP and androgen-independent PC-3 prostate cancer cell lines in this study (30) . We report a novel form of interaction between growth factor and cAMP-dependent signaling, in which cAMP elevation potentiates the ability of growth factors to activate the MAPKs ERK1 and ERK2. We also show that activation of MAPK by suboptimal levels of EGF can be potentiated by IL-6 and PMA. The results suggest that autocrine stimulation of cancer cell signaling is dependent on the combinations of extracellular agonists, beyond what would be predicted based on the activities of single agents.
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MATERIALS AND METHODS |
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Antibodies and Other Reagents.
Rabbit anti-phospho-MAPK antibodies were raised against a synthetic peptide corresponding to the MAPK phosphorylation site [CTGFLT(p)EY(p)VATR] conjugated to keyhole limpet hemacyanin (Pierce, Rockford, IL) and affinity purified negatively against the unphosphorylated peptide and positively against the phosphopeptide (32)
. Other antibodies were purchased from the following sources: anti-ERK2 from Upstate Biotechnology (Lake Placid, NY); anti-Rap1/Krev-1 (121), anti-Raf-B (C-19), and anti-Raf-1 (C-20) from Santa Cruz Biotechnology (Santa Cruz, CA); anti-FLAG M2 gel from Kodak Scientific Imaging Systems (Rochester, NY).
Ni-NTA Agarose was from Qiagen (Santa Clarita, CA). EGF was from Upstate Biotechnology. FSK and dibutyryl cAMP were from Sigma Chemical Co. (St. Louis, MO). Epinephrine, isoproterenol, PMA, IL-6, and A23187 were from Calbiochem (La Jolla, CA). PTHrP, VIP, calcitonin, and bombesin were from Peninsula Laboratories (Belmont, CA).
Plasmids and Transfection.
His-Rap (wild type), His-RapV12, and His-RapN17 plasmids were described previously (15)
. pcDNA3 was from Invitrogen (Carlsbad, CA). FLAG-tagged ERK2 was provided by Dr. S. T. Eblen of the University of Virginia. Transfections were performed using N-[1-(2,3-dioleoyloxyl)propyl]-N,N,N-trimethylammoniummethyl sulfate according to the instructions of the manufacturer (Boehringer Mannheim, Indianapolis, IN). Briefly, 106 LNCaP cells were plated on 100-mm Petri dishes and incubated in RPMI 1640 with 10% FBS for 2 days. Five µg of FLAG-ERK2 were mixed with 10 µg of either His-Rap (wild type), His-RapV12, His-RapN17, or pcDNA3 plasmid and transfection was performed in the presence of 10% FBS. After a 6-h incubation, cells were rinsed with fresh medium and kept in serum-free RPMI 1640 for 12–16 h prior to stimulation as described below.
Activation of MAPKs, Immunoprecipitation of Proteins, and Immunoblotting.
Cells on 100- or 60-mm dishes were starved in serum-free RPMI 1640 for 12–16 h and subsequently treated with various agents or control vehicle as indicated. Preparation of cell extracts and Western blotting were performed as described (33)
. Anti-phospho-MAPK antibody was used to detect MAPK phosphorylation and activation (32)
. For the cotransfection experiments, LNCaP cells were transfected and starved as described above. About 400 µg of cell lysate were used for immunoprecipitations. FLAG-ERK2 was immunoprecipitated using anti-FLAG M2 gel according to the instructions of the manufacturer (Kodak). Histidine-tagged Rap1 was precipitated with Ni-NTA agarose (Qiagen). Western blotting analysis was performed following precipitation of the tagged proteins.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). MAPK activity was also stimulated to various levels by hormones and hormone analogues that are known to increase intracellular cAMP, including epinephrine, isoproterenol, PTHrP, VIP, calcitonin, and bombesin, as well as by the cAMP analogue dibutyryl cAMP (Fig. 1A)
and the adenylate cyclase activator, FSK (Fig. 1B)
. At the optimum concentration, EGF (10 ng/ml) was a far more potent MAPK activator than were the agonists that elevate cAMP (data not shown). More dramatically, elevation of cAMP level substantially potentiated the ability of suboptimal concentrations of EGF to activate MAPK (Fig. 1)
. We found that, when cAMP was elevated in LNCaP cells, 1 ng/ml EGF activated MAPK almost as well as did 10 ng/ml EGF in cells with basal levels of cAMP (data not shown).
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, indicating that PKA is required for the action of FSK. The effect of H-89 was specific to PKA because H-89 had no inhibitory effect on EGF-mediated MAPK activation (Fig. 1B)
. However, activation of MAPK by either EGF or FSK was completely blocked by the specific MEK inhibitor PD098059, suggesting that MEK activation is required in both cases.
Activation of MAPK by EGF Is Potentiated by cAMP through a Rap1/B-Raf-dependent Pathway.
Rap1, a Ras-related small GTP-binding protein, has been shown to be able to activate B-Raf and, hence, MAPK in response to PKA in PC12 neuronal cells (15)
. To investigate the potential involvement of the Rap1/B-Raf pathway in the potentiating effects of cAMP on EGF activation of MAPK in LNCaP cells, we first examined the expression of Rap1, B-Raf, and Raf-1 in this cell line. As with PC12 cells, LNCaP cells expressed Rap1, Raf-1, and B-Raf (Fig. 2)
. Treatment of LNCaP cells with FSK induced a bandshift of the endogenous Rap1 (data not shown), indicating that Rap1 was phosphorylated and activated by PKA in LNCaP cells. To investigate whether activation of Rap1 was responsible for the effect of cAMP in potentiating the ability of EGF to activate MAPK, the actions of RapV12, a mutationally activated form of Rap1 in which Gly-12 is mutated to Val, and RapN17, a dominant-negative mutant (15)
, were examined. As shown in Fig. 3
, RapV12 was able to mimic the effect of elevated cAMP in potentiating MAPK activation by EGF, indicating that activation of Rap1 is sufficient to potentiate MAPK activation by EGF. RapN17 was able to block the effect of FSK in potentiating the effects of EGF in MAPK activation, indicating that Rap1 function is required. Similar results were observed when dibutyryl cAMP or epinephrine was used instead of FSK in the RapN17 experiment (data not shown). Taken together, these results indicate that cAMP potentiates the effects of EGF in activating MAPK through a Rap1-dependent pathway.
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We compared the effect of cAMP on MAPK activation in LNCaP, PC-3, and fibroblast Rat-1 cells (Fig. 4)
. In PC-3 cells, MAPK was strongly activated by EGF, but pretreatment with FSK reproducibly caused a modest decrease in EGF-mediated MAPK activation. The basal activity of MAPK was higher in PC-3 cells than in LNCaP cells, and the basal MAPK activity of PC3 cells was inhibited by elevated cAMP. In Rat-1 fibroblast cells, both basal and EGF-mediated MAPK activation were completely abolished by pretreatment with FSK, as reported previously (9)
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, B-Raf expression was highest in LNCaP, lower in PC-3, and lowest in Rat-1 cells. All cell lines expressed high levels of Raf-1. Thus, consistent with results reported previously (15)
, the ratio of B-Raf/Raf-1 expression correlates with the effects of cAMP on MAPK activation. Expression of Rap1 was lower in the prostate cells LNCaP and PC-3 than in Rat-1, NIH3T3, and PC12 (Fig. 2)
, but this appears to be unrelated to the signaling effects of cAMP on the MAPK pathway because overexpression of wild-type Rap1 did not enhance the ability of FSK to activate the MAPK cascade (Fig. 3)
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Potentiation of MAPK Signaling by cAMP and Combinatorial Extracellular Agonists.
Because prostate cancer cells in vivo are exposed to diverse agonists, we wished to determine whether elevation of cAMP could potentiate effects of all or only some of these MAPK activators. Fig. 5A
shows that serum, IL-6, PMA, and the calcium ionophore A23187 were able to activate MAPK in LNCaP cells, although only PMA was as effective as EGF. Strikingly, however, FSK potentiated MAPK activation not only by EGF (Fig. 1)
but by serum and IL-6 as well. These are all receptor-dependent activators of MAPK. However, FSK inhibited the effect of the receptor-independent MAPK activators PMA and A23187. Fig. 5B
shows that activation of MAPK by suboptimal EGF was also potentiated by IL-6 and PMA. Although, in this experiment, the response of the LNCaP cells to 1 ng/ml EGF was less robust than we usually observe, the superadditive effect is easily seen and has been reproduced four times. We did not observe a potentiating effect on MAPK activation by EGF combined with basic FGF, acidic FGF, or keratinocyte growth factor, although all three growth factors were effective MAPK activators (data not shown).
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DISCUSSION |
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MAPK and cAMP can cross-talk either concordantly or antagonistically and because of the central role of MAPK in growth, differentiation, and movement of cells, we have examined the ways that these pathways interact in prostate cancer cells. In addition, we have examined the cross-talk between EGF-induced signaling and signals induced by other mitogenic agonists. In this study, we found that growth factors linked to Ras, as well as agents that elevate cAMP, are able to cause activation of MAPK in LNCaP prostate cancer cells, although EGF was a much more potent activator at optimal concentrations (data not shown). However, at submaximal concentrations of EGF, elevation of cAMP acted to dramatically potentiate the ability of the growth factor to activate MAPK.
In PC12 pheochromocytoma cells, elevation of cAMP activates MAPK by a pathway dependent on Rap1 and B-Raf (15) . In this system, elevated cAMP activates PKA, which phosphorylates and activates the small GTP-binding protein Rap1, which, in turn, activates B-Raf and inhibits Ras and c-Raf-1. Consistent with this scheme, we find that LNCaP cells display high levels of B-Raf. As reported previously (9) , cAMP inhibited both basal and EGF-mediated MAPK activation in Rat-1 fibroblast cells, and these cells express a very low level of B-Raf. In the androgen-independent prostate cancer cell PC-3, the B-Raf expression level was intermediate, and MAPK activation by EGF was only slightly inhibited by cAMP. Because Raf-1 was expressed at equivalent levels in all cell lines used in this study, it is possible that the ratio of B-Raf to Raf-1 is important in determining the effect of cAMP on MAPK activation in prostate cancer cells, as suggested previously for neuronal cells (15 , 36) .
The hypothesis proposed previously for neuronal cells (15 , 36) , however, does not fully explain the fact that cAMP elevation only weakly activated MAPK by itself but dramatically potentiated the activation of MAPK by submaximal levels of growth factors. Nevertheless, some of the same molecular players are involved in MAPK signaling in LNCaP as in PC12 cells. We showed that the synergistic effects of cAMP elevation on activation of MAPK in LNCaP cells also depended on Rap1. Moreover, the LNCaP cells displayed high levels of B-Raf. How could the PKA signal be synergistic with EGF (as well as IL-6 and serum) in MAPK activation but still be antagonistic to a MAPK activation pathway that goes through PKC and, probably, Raf-1? We propose that Rap1, although essential for activation of the MAPK pathway in the presence of cAMP, is unable to fully activate the pathway without the participation of an additional, receptor-initiated signal. This additional signal could be active Ras or some other signal upstream of Raf. For example, it is reasonable to propose as a working hypothesis that Rap1 activated by PKA recruits B-Raf to the plasma membrane, where it is activated by a second signal (such as a kinase), which is, in turn, activated by the growth factor-generated signal. In PC12 cells, this second signal could be constitutive, rendering the activation of the MAPK pathway solely dependent on recruitment of B-Raf to the membrane. Another possibility (the two possibilities are not mutually exclusive) is that full activation of Rap1 by cAMP requires additional signals upstream of Rap1. Recent studies have identified potential Rap exchangers and adapters that are activated by growth factors in other cell types (37) . Their role in cAMP signaling has not been fully elucidated.
We found that various agonists in addition to EGF were able to activate MAPK in LNCaP cells, including IL-6, serum, PMA, and the calcium ionophore A23187 (Fig. 5)
. Strikingly, the agonists that activate the MAPK pathway via receptor activation (EGF, IL-6, and serum), all were potentiated by elevated cAMP, whereas activation of MAPK by PMA or A23187, which act intracellularly, was antagonized by cAMP. IL-6 activates MAPK in PC12 cells through JAKs and a tyrosine phosphatase SHP-2, which signals via the Grb2-SOS-Ras pathway (38)
. PMA activates MAPK in NIH3T3 fibroblasts by activating PKC, which, in turn, is believed to phosphorylate and activate Raf-1 (39)
, perhaps in a Ras-dependent manner (40
, 41)
. Increasing intracellular Ca2+ results in activation of the PKC pathway, which could, in turn, activate MAPK (42
, 43) . In neuronal cells, calcium activates Ras through a neuronal exchange factor, Ras-GRF (44)
. Because both PMA and Ca2+ are capable of activating the MAPK pathway via PKC-mediated activation of Raf-1, it is reasonable to hypothesize that these intracellular activators bypass the Rap1/B-Raf pathway and, thus, display antagonistic cross-talk between cAMP and MAPK, as is seen in fibroblasts. Fig. 6
schematizes the ways in which EGF, PKA, and PMA signaling might interact in MAPK activation. The implication of this scheme is that the consequences of cross-talk between the PKA and MAPK pathways will vary not only with the cell type but also with the agonist. This is consistent with the role of MAPK as an effector of extracellular regulation whose functional consequences vary with biological context. It also is consistent with our observation that activation of MAPK by EGF is potentiated by IL-6 or PMA.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This work was supported by a CaPCURE award and NIH Grants CA 12467, CA 76500, and GM 47332. 
2 To whom requests for reprints should be addressed, at Department of Microbiology, University of Virginia Health Sciences Center, Charlottesville, VA 22908.
3 The abbreviations used are: MAPK, mitogen-activated protein kinase; ERK, extracellularly regulated kinase; PKA, protein kinase A; MEK, MAPK kinase; EGF, epidermal growth factor; TGF-, transforming growth factor-; IL-6, interleukin 6; FGF, fibroblast growth factor; VIP, vasoactive intestinal polypeptide; PMA, phorbol 12-myristate 13-acetate; FBS, fetal bovine serum; FSK, forskolin; PTHrP, parathyroid hormone-related peptide; PKC, protein kinase C.
Received 6/15/98. Accepted 10/29/98.
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Z. Ni, W. Lou, E. S. Leman, and A. C. Gao Inhibition of Constitutively Activated Stat3 Signaling Pathway Suppresses Growth of Prostate Cancer Cells Cancer Res., March 1, 2000; 60(5): 1225 - 1228. [Abstract] [Full Text]
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 A. C. Gao, W. Lou, and J. T. Isaacs Enhanced GBX2 Expression Stimulates Growth of Human Prostate Cancer Cells via Transcriptional Up-Regulation of the Interleukin 6 Gene Clin. Cancer Res., February 1, 2000; 6(2): 493 - 497. [Abstract] [Full Text]
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H. J. Schaeffer and M. J. Weber Mitogen-Activated Protein Kinases: Specific Messages from Ubiquitous Messengers Mol. Cell. Biol., April 1, 1999; 19(4): 2435 - 2444. [Full Text] [PDF]
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D. Gioeli, J. W. Mandell, G. R. Petroni, H. F. Frierson Jr., and M. J. Weber Activation of Mitogen-Activated Protein Kinase Associated with Prostate Cancer Progression Cancer Res., January 1, 1999; 59(2): 279 - 284. [Abstract] [Full Text] [PDF]
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J. M. Schmitt and P. J. S. Stork beta 2-Adrenergic Receptor Activates Extracellular Signal-regulated Kinases (ERKs) via the Small G Protein Rap1 and the Serine/Threonine Kinase B-Raf J. Biol. Chem., August 11, 2000; 275(33): 25342 - 25350. [Abstract] [Full Text] [PDF]
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J. F. Rebhun, A. F. Castro, and L. A. Quilliam Identification of Guanine Nucleotide Exchange Factors (GEFs) for the Rap1 GTPase. REGULATION OF MR-GEF BY M-Ras-GTP INTERACTION J. Biol. Chem., November 3, 2000; 275(45): 34901 - 34908. [Abstract] [Full Text] [PDF]
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