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Advances in Brief |
Departments of Microbiology and Cancer Center [D. G., M. J. W.], Pathology [J. W. M., H. F. F.], and Health Evaluation Services [G. R. P.], University of Virginia Health Sciences Center, Charlottesville, Virginia 22908
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ABSTRACT |
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 Top ABSTRACT IntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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Introduction |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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, IGF-I, interleukin 6, keratinocyte growth factor, and other FGF family members are expressed in advanced prostate cancers and are believed to be important in fueling androgen-independent growth. Notably, prostate cancer progression is associated with a transition from a paracrine to an autocrine relationship between the EGF receptor and TGF: in primary prostatic tumors, the neoplastic cells express EGF receptor, and the surrounding stromal cells express TGF, whereas in advanced disease, the neoplastic cells co-express the EGF receptor and TGF (2)
. In addition to an increase in the presence of peptide growth factors, elevated levels of neuropeptides produced by neuroendocrine cells have been associated with prostate cancer progression and decreased patient survival (3
, 4)
. Along with the increased production of neuropeptides and growth factors, increased expression of proliferation markers (e.g., proliferating cell nuclear antigen, KI-67, and MIB-1 ) correlates with advanced tumor grade and stage in prostate cancer (5)
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The growth factors and receptors associated with prostate cancer progression regulate cell growth at least partly through the mediation of Ras family members. These small GTP-binding proteins initiate a signal transduction cascade of successive phosphorylations leading to the activation of various effectors, including MAP kinases (6)
. Neuropeptides may also influence the activation of MAP kinase by peptide growth factors. A recent study showed that when androgen-responsive LNCaP prostate cancer cells were exposed to suboptimal levels of EGF, elevation of cAMP by neuropeptides dramatically potentiated activation of MAP kinase (7)
. If signaling by peptide growth factors, such as TGF, and chronic autocrine stimulation of the Ras pathway play a causal role in prostate cancer progression, one might predict increased activation of downstream kinases, such as MAP kinase, in advanced prostate cancer specimens.
Although few studies have examined the activation of MAP kinase in human tumors, elevated levels of activated MAP kinase have been detected in carcinomas of the kidney, liver, and prostate using electophoretic mobility shift and immune-complex kinase assays on tumor tissue homogenates (8, 9, 10) . However, analysis of tumor homogenates may be problematic because nonneoplastic cells are included in the assessment of protein activity. Activation state-specific antibodies have recently emerged as a means to test for activation of specific signal transduction proteins at the cellular level.
In the present study, activation of MAP kinase was assessed using a phospho-MAP kinase antibody specific for the dually phosphorylated and activated MAP kinases ERK1 and ERK2. The results described here show an increase in MAP kinase activation with advanced tumor grade and stage, consistent with the hypothesis that prostate cancer progression is associated with chronic stimulation of the Ras signaling pathway.
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Materials and Methods |
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Antibodies.
The antibody specific for the dually phosphorylated MAP kinases, ERK1 and ERK2, has been previously described (12)
. Briefly, rabbit polyclonal antiserum was raised against the phosphopeptide CHTGFLpTEpYVATR (Quality Controlled Biochemicals, Hopkintown, MA). Affinity purification of antisera was performed by negative selection over a column of nonphosphorylated peptide and subsequent positive selection over a column of dually phosphorylated peptide. Antiserum was used at a concentration of 0.5 µg/ml for immunohistochemistry. Affinity purified rabbit anti-ERK1/ERK2 (ZS61–7400, Zymed Laboratories, San Francisco, CA), which recognizes both the phosphorylated and nonphosphorylated forms of ERK1 and ERK2, was used at a concentration of 2.5 µg/ml for immunohistochemistry.
Immunohistochemistry.
Immunohistochemical conditions were optimized using the LNCaP prostate cancer cell line. Serum-starved LNCaP cells were treated with EGF or vehicle for 30 min and fixed in zinc-buffered formalin. To emulate tissue, LNCaP cells were centrifuged, embedded in agar, and processed routinely into paraffin. Under the optimized conditions detailed below, untreated LNCaP cells showed little to no phospho-MAP kinase staining, whereas EGF-treated LNCaP cells showed intense nuclear and cytoplasmic phospho-MAP kinase immunoreactivity (data not shown).
After deparaffinization of unstained human prostate cancer specimens in xylene and alcohol, endogenous peroxidase activity was quenched by 30 min incubation in 0.5% hydrogen peroxide/methanol. Following hydration, microwave epitope retrieval was performed in 10 mM citrate buffer, pH 6.0, for 10 min at 1.15 kW. Peptide competition experiments were performed by preincubating diluted phospho-specific MAP kinase antisera (0.5 µg/ml) for 1 h at room temperature with a 100 µM concentration of either the dually phosphorylated peptide or the nonphosphorylated peptide. Immunohistochemistry was performed using the avidin-biotin-peroxidase complex method according to the manufacturer’s instructions (Vectastain Elite kit, Vector Laboratories, Burlingame, CA). Biotinylated goat anti-rabbit was used as the secondary antibody and diaminobenzidine was used as the chromogen. Sections were counterstained with hematoxylin.
Digital images for photomicroscopy were acquired with a Dage DC-330 three-color charge-coupled device camera controlled by Image Pro-Plus software. Adjustments in image brightness and contrast were performed identically and in parallel for the images presented using Adobe Photoshop 4.0. Composite images were made using Adobe Illustrator 6.0 and printed on a Codonics NP-1600 dye sublimation printer.
Statistics.
A generalized rank test for trend with an assumed known order alternative was used to test, a priori, whether (a) higher levels of activated MAP kinase in samples were associated with higher Gleason scores, and (b) higher levels of activated MAP kinase in samples were associated with more advanced tumor stage. The generalized case III rank test for trend (13)
provided the most power to test the particular alternative of interest (i.e., higher levels of activated MAP kinase in tumors with higher Gleason scores).
An exact 
2 test was used to test whether levels of activated MAP kinase (zero, low, or high) differed between stage IV primary and metastatic prostate tumors. The power to detect a difference in the range of the observed effect size (0.32) was less than 35%.
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Results |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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Adjacent nonneoplastic prostatic epithelium showed little or no staining with activated MAP kinase antiserum; however, virtually all of these samples displayed some level of activated MAP kinase immunoreactivity in a fraction of the glandular epithelial cells (Fig. 1A)
. In general, basal cells showed activated MAP kinase staining more frequently than secretory cells, and at times, the basal cell layer showed a nearly continuous staining pattern. Activated MAP kinase was frequently detected in the surrounding smooth muscle stroma, endothelium, and peripheral nerves. Lymphocytes were virtually always negative with only the rare cell staining for activated MAP kinase. In most cells positive for MAP kinase immunoreactivity, both intense nuclear and more diffuse cytoplasmic staining was apparent.
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10% tumor cells positive). This scoring system was highly reproducible and virtually bimodal. Most samples with low phospho-MAP kinase staining displayed less than 5% positive tumor cell nuclei and most samples with high phospho-MAP kinase staining showed greater than 20% positive tumor cell nuclei. We noted no overt differences in staining in foci of high grade prostate intraepithelial neoplasm compared with adjacent invasive carcinoma. Immunoreactive smooth muscle cells and immunonegative lymphocytes acted as internal positive and negative controls for each sample examined. Fig. 1, B-D
, shows three specimens with high levels of activated MAP kinase.
To confirm the specificity of the phospho-MAP kinase antibody, control experiments were performed on a subset of tumors (n = 10). Immunohistochemistry using preimmune affinity purified IgG was negative (data not shown). Staining with an antibody to total MAP kinase revealed cytoplasmic immunostaining in the majority of epithelial and stromal cells independent of phospho-MAP kinase activation (compare Fig. 2, A and B
, to Fig. 2, C and D
). In addition, nuclear staining for total MAP kinase was occasionally found in areas of active MAP kinase (Fig. 2D)
. This subcellular distribution of total and active MAP kinase is consistent with the current understanding of MAP kinase signaling: MAP kinase is activated in the cytoplasm and subsequently translocates to the nucleus. Preincubation of the phospho-MAP kinase antibody with the dually phosphorylated peptide virtually eliminated immunoreactivity (compare Fig. 2, C and E
); staining of activated MAP kinase was not blocked when the phospho-MAP kinase antibody was preincubated with the nonphosphorylated peptide (compare Fig. 2, C and F
). The ability of the dually phosphorylated peptide to block immunoreactivity was specific to the phospho-MAP kinase antibody, as the phosphorylated peptide was unable to block total MAP kinase staining (data not shown).
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and 2
. The level of activated MAP kinase increased with increasing Gleason score (P < 0.001). High levels of activated MAP kinase were seen in 70% of tumors with a Gleason score of 8–10, whereas low or no activated MAP kinase was seen in 89% of tumors with a Gleason score of 
6. The levels of activated MAP kinase also increased with increasing tumor stage (P = 0.017); 66% of stage IV tumors had high levels of activated MAP kinase, and 83% of stage II tumors had low or no activated MAP kinase. These data suggest an increase in the activation of the MAP kinase signal transduction pathway as prostate cancer progresses to a more advanced disease.
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Our data set of primary and metastatic prostate tumors analyzed above does not enable examination of the relationship between MAP kinase activation and androgen ablation therapy. However, the case histories of two patients not included in the above analyses (because we have repeated measures for these patients) suggest that elevated MAP kinase signaling in tumor cells may be selected for during androgen ablation therapy. One patient presented with urinary obstruction due to stage II adenocarcinoma of the prostate (Gleason score, 10) . Staining of the TURP done at this time showed no staining for activated MAP kinase. Eleven months later, the patient underwent bilateral orchiectomy, and 7 months following orchiectomy, the patient again presented with urinary obstruction. Analysis of this post-androgen ablation TURP showed high levels of activated MAP kinase. The second patient had an orchiectomy after metastatic deposits were found in his retroperitoneal lymph node dissection. There was no activated MAP kinase detected in this lymph node metastasis. Thirteen years later, the patient underwent a TURP to relieve a urinary obstruction. As with the first patient, this patient’s post-androgen ablation TURP showed high levels of activated MAP kinase. Thus, the data from these patients suggest that activation of the MAP kinase signal transduction pathway and the development of androgen-independent prostate cancer may be related.
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Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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We have used the emerging technology of activation state-specific antibodies to directly examine activation of the MAP kinase signaling pathway in prostate cancer. The activation state of ERK1 and ERK2 was assessed at the cellular level by using an antibody that specifically recognizes dually phosphorylated ERK1 and ERK2. A similar approach was recently used to demonstrate activation of MAP kinase in a broad range of glial tumors (astrocytic tumors, glioblastomas, and oligodendrogliomas) (17) . Notably, oligodendrogliomas showed an increase in MAP kinase activation with malignant progression.
Previous studies have demonstrated a role for MAP kinase activation in cell proliferation (18) . The data reported here show elevated levels of active MAP kinase in high-grade and advanced stage prostate tumors. These observations, combined with previous reports demonstrating increased expression of cell proliferation markers as prostate cancer progresses to a more advanced and androgen-independent disease, suggest that activation of MAP kinase in prostate cancer is linked to cell proliferation (5) .
Although the role of MAP kinase in cell proliferation has been established in the literature, our data suggest that elevated MAP kinase activation may also be important in the acquisition of androgen-independent prostate cancer growth. Analysis of two patients’ tumor samples showed no activation of MAP kinase before androgen ablation therapy and high levels of activated MAP kinase following androgen ablation treatment, suggesting that MAP kinase is activated in hormone refractory tumors.
Other studies have suggested that growth factor receptor signaling may play a role in the development of androgen-independent prostate cancer, supporting a possible role for MAP kinase activation in the development of androgen refractory prostate tumors. Voeller et al. (19) showed that activation of Ras is sufficient to induce androgen-independent growth of prostate cancer cells; expression of an activated v-RasH in the androgen-responsive LNCaP prostate cancer cell line enabled growth in the absence of androgen (19) . This suggests that activation of Ras signaling can facilitate the progression of prostate cancer from an androgen-dependent to an androgen-independent state. Because Ras mutations are uncommon in prostate tumors, we propose that the transition from paracrine to autocrine loops of growth factor production and signaling during prostate cancer progression results in the chronic stimulation of the Ras pathway which helps drive prostate cancer cells to an androgen-independent state. Our observation of elevated levels of activated MAP kinase in high-grade and advanced-stage prostate tumors is consistent with chronic Ras signaling.
Previous studies examining the influence of growth factor signaling on AR activity have provided clues as to how continual stimulation of signal transduction pathways may affect androgen-independent growth. Culig et al. (20) demonstrated that IGF-I, EGF, and keratinocyte growth factor were able to induce AR-mediated reporter gene transcription using DU145 cells, a prostate cancer cell line that expresses neither AR nor PSA, and a cotransfection assay with an AR expression vector and chloramphenicol acetyltransferase reporter constructs (20) . Growth factor-induced reporter gene expression was dependent on cotransfection of the AR expression construct and was blocked by the AR antagonist casodex. In the same study, activation of endogenous AR by IGF-I in LNCaP cells was demonstrated using endogenous PSA production as a marker. Again, the effect of IGF-I on PSA production was blocked by casodex. These experiments suggest that growth factor signaling can regulate androgen responsive genes by a mechanism that is AR dependent and androgen independent. This parallels discoveries on estrogen receptor regulation in which EGF activates the estrogen receptor in breast cancer cells via activation of MAP kinase, which directly phosphorylates the estrogen receptor on Ser118 (21) .
Additional studies by Nazareth and Weigle (22) demonstrated that the AR can be activated by a protein kinase A activator in the absence of androgen (22) . This activation can be blocked by a protein kinase A inhibitor peptide and the AR antagonists casodex and flutamide, indicating that the activation effect was due to PKA and dependent on AR. More recently it has been demonstrated that neuropeptides, which activate PKA, sensitize prostate cancer cells to signaling by peptide growth factors, such as EGF (6) .
Thus, we propose that during prostate cancer progression and androgen ablation therapy, there may be a microenvironment in which peptide growth factors and neuropeptides activate signal transduction pathways that influence AR activity and help drive prostate cancer cells to an androgen-independent state. Our observation of elevated levels of activated MAP kinase in advanced prostate tumors begins to address the mechanism of androgen-independent growth of prostate tumors cells and suggests potential targets for blocking or reversing progression to androgen independence.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This work was supported by Grants GM47332, CA76500, and CA39076 from the United States Public Health Service and by a gift from CaP CURE (to M. J. W.). D. G. was supported by NCI T32 CA09109 and the American Foundation for Urologic Disease/Scott Fund. 
2 To whom requests for reprints should be addressed.
3 The abbreviations used are: EGF, epidermal growth factor; TGF, transforming growth factor ; IGF-I, insulin-like growth factor I; FGF, fibroblast growth factor; MAP, mitogen-activated protein; MKP-1, MAP kinase phosphatase 1; ERK, extracellular-regulated kinase; TURP, transurethral resection of prostate; JNK, c-Jun N-terminal kinase; PSA, prostate-specific antigen; AR, androgen receptor.
Received 10/14/98. Accepted 11/25/98.
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P. M Ghosh, S. N Malik, R. G Bedolla, Y. Wang, M. Mikhailova, T. J Prihoda, D. A Troyer, and J. I Kreisberg Signal transduction pathways in androgen-dependent and -independent prostate cancer cell proliferation Endocr. Relat. Cancer, March 1, 2005; 12(1): 119 - 134. [Abstract] [Full Text] [PDF]
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E. Unni, S. Sun, B. Nan, M. J. McPhaul, B. Cheskis, M. A. Mancini, and M. Marcelli Changes in Androgen Receptor Nongenotropic Signaling Correlate with Transition of LNCaP Cells to Androgen Independence Cancer Res., October 1, 2004; 64(19): 7156 - 7168. [Abstract] [Full Text] [PDF]
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R. Foley, D. Hollywood, and M. Lawler Molecular pathology of prostate cancer: the key to identifying new biomarkers of disease Endocr. Relat. Cancer, September 1, 2004; 11(3): 477 - 488. [Abstract] [Full Text] [PDF]
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A. R. Uzgare and J. T. Isaacs Enhanced Redundancy in Akt and Mitogen-activated Protein Kinase-induced Survival of Malignant versus Normal Prostate Epithelial Cells Cancer Res., September 1, 2004; 64(17): 6190 - 6199. [Abstract] [Full Text] [PDF]
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H. Li, T. J. Ahonen, K. Alanen, J. Xie, M. J. LeBaron, T. G. Pretlow, E. L. Ealley, Y. Zhang, M. Nurmi, B. Singh, et al. Activation of Signal Transducer and Activator of Transcription 5 in Human Prostate Cancer Is Associated with High Histological Grade Cancer Res., July 15, 2004; 64(14): 4774 - 4782. [Abstract] [Full Text] [PDF]
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 D. C. Lev, A. Onn, V. O. Melinkova, C. Miller, V. Stone, M. Ruiz, E. C. McGary, H. N. Ananthaswamy, J. E. Price, and M. Bar-Eli Exposure of Melanoma Cells to Dacarbazine Results in Enhanced Tumor Growth and Metastasis In Vivo J. Clin. Oncol., June 1, 2004; 22(11): 2092 - 2100. [Abstract] [Full Text] [PDF]
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S. Vicent, M. Garayoa, J. M. Lopez-Picazo, M. D. Lozano, G. Toledo, F. B. J. M. Thunnissen, R. G. Manzano, and L. M. Montuenga Mitogen-Activated Protein Kinase Phosphatase-1 Is Overexpressed in Non-Small Cell Lung Cancer and Is an Independent Predictor of Outcome in Patients Clin. Cancer Res., June 1, 2004; 10(11): 3639 - 3649. [Abstract] [Full Text] [PDF]
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M. Rahman, H. Miyamoto, and C. Chang Androgen Receptor Coregulators in Prostate Cancer: Mechanisms and Clinical Implications Clin. Cancer Res., April 1, 2004; 10(7): 2208 - 2219. [Full Text] [PDF]
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 Y. Daaka G Proteins in Cancer: The Prostate Cancer Paradigm Sci. Signal., January 20, 2004; 2004(216): re2 - re2. [Abstract] [Full Text] [PDF]
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P. V. Nantermet, J. Xu, Y. Yu, P. Hodor, D. Holder, S. Adamski, M. A. Gentile, D. B. Kimmel, S.-i. Harada, D. Gerhold, et al. Identification of Genetic Pathways Activated by the Androgen Receptor during the Induction of Proliferation in the Ventral Prostate Gland J. Biol. Chem., January 9, 2004; 279(2): 1310 - 1322. [Abstract] [Full Text] [PDF]
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J. W. Mandell Phosphorylation State-Specific Antibodies: Applications in Investigative and Diagnostic Pathology Am. J. Pathol., November 1, 2003; 163(5): 1687 - 1698. [Abstract] [Full Text] [PDF]
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K. Jorgensen, R. Holm, G. M. Maelandsmo, and V. A. Florenes Expression of Activated Extracellular Signal-Regulated Kinases 1/2 in Malignant Melanomas: Relationship with Clinical Outcome Clin. Cancer Res., November 1, 2003; 9(14): 5325 - 5331. [Abstract] [Full Text] [PDF]
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 E. C. Woodhouse, A. Fisher, R. W. Bandle, B. Bryant-Greenwood, L. Charboneau, E. F. Petricoin III, and L. A. Liotta Drosophila screening model for metastasis: Semaphorin 5c is required for l(2)gl cancer phenotype PNAS, September 30, 2003; 100(20): 11463 - 11468. [Abstract] [Full Text] [PDF]
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A. L. Bookout, A. E. Finney, R. Guo, K. Peppel, W. J. Koch, and Y. Daaka Targeting G{beta}{gamma} Signaling to Inhibit Prostate Tumor Formation and Growth J. Biol. Chem., September 26, 2003; 278(39): 37569 - 37573. [Abstract] [Full Text] [PDF]
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Y. Tanaka, M. V. Gavrielides, Y. Mitsuuchi, T. Fujii, and M. G. Kazanietz Protein Kinase C Promotes Apoptosis in LNCaP Prostate Cancer Cells through Activation of p38 MAPK and Inhibition of the Akt Survival Pathway J. Biol. Chem., September 5, 2003; 278(36): 33753 - 33762. [Abstract] [Full Text] [PDF]
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L. Zhang, M. Johnson, K. H. Le, M. Sato, R. Ilagan, M. Iyer, S. S. Gambhir, L. Wu, and M. Carey Interrogating Androgen Receptor Function in Recurrent Prostate Cancer Cancer Res., August 1, 2003; 63(15): 4552 - 4560. [Abstract] [Full Text] [PDF]
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B. Govindarajan, M. C. Mizesko, M. S. Miller, H. Onda, M. Nunnelly, K. Casper, D. Brat, C. Cohen, and J. L Arbiser Tuberous Sclerosis-associated Neoplasms Express Activated p42/44 Mitogen-activated Protein (MAP) Kinase, and Inhibition of MAP Kinase Signaling Results in Decreased in Vivo Tumor Growth Clin. Cancer Res., August 1, 2003; 9(9): 3469 - 3475. [Abstract] [Full Text] [PDF]
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Y. Hu, M. Bally, W. H. Dragowska, and L. Mayer Inhibition of Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinase Kinase Enhances Chemotherapeutic Effects on H460 Human Non-Small Cell Lung Cancer Cells through Activation of Apoptosis Mol. Cancer Ther., July 1, 2003; 2(7): 641 - 649. [Abstract] [Full Text] [PDF]
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 J. R. Stewart, M. C. Artime, and C. A. O'Brian Resveratrol: A Candidate Nutritional Substance for Prostate Cancer Prevention J. Nutr., July 1, 2003; 133(7): 2440S - 2443. [Abstract] [Full Text] [PDF]
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V. Sung, W. Luo, D. Qian, I. Lee, B. Jallal, and M. Gishizky The Ste20 Kinase MST4 Plays a Role in Prostate Cancer Progression Cancer Res., June 15, 2003; 63(12): 3356 - 3363. [Abstract] [Full Text] [PDF]
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Y.-W. Lin, S.-M. Chuang, and J.-L. Yang ERK1/2 Achieves Sustained Activation by Stimulating MAPK Phosphatase-1 Degradation via the Ubiquitin-Proteasome Pathway J. Biol. Chem., June 6, 2003; 278(24): 21534 - 21541. [Abstract] [Full Text] [PDF]
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J. S. Taub, R. Guo, L. M. F. Leeb-Lundberg, J. F. Madden, and Y. Daaka Bradykinin Receptor Subtype 1 Expression and Function in Prostate Cancer Cancer Res., May 1, 2003; 63(9): 2037 - 2041. [Abstract] [Full Text] [PDF]
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R. E. Bakin, D. Gioeli, R. A. Sikes, E. A. Bissonette, and M. J. Weber Constitutive Activation of the Ras/Mitogen-activated Protein Kinase Signaling Pathway Promotes Androgen Hypersensitivity in LNCaP Prostate Cancer Cells Cancer Res., April 15, 2003; 63(8): 1981 - 1989. [Abstract] [Full Text] [PDF]
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R. P. Singh, C. Agarwal, and R. Agarwal Inositol hexaphosphate inhibits growth, and induces G1 arrest and apoptotic death of prostate carcinoma DU145 cells: modulation of CDKI-CDK-cyclin and pRb-related protein-E2F complexes Carcinogenesis, March 1, 2003; 24(3): 555 - 563. [Abstract] [Full Text] [PDF]
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 G. M. Carbone, E. M. McGuffie, A. Collier, and C. V. Catapano Selective inhibition of transcription of the Ets2 gene in prostate cancer cells by a triplex-forming oligonucleotide Nucleic Acids Res., February 1, 2003; 31(3): 833 - 843. [Abstract] [Full Text] [PDF]
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 K. D. Burroughs, J. Oh, J. C. Barrett, and R. P. DiAugustine Phosphatidylinositol 3-Kinase and Mek1/2 Are Necessary for Insulin-Like Growth Factor-I-Induced Vascular Endothelial Growth Factor Synthesis in Prostate Epithelial Cells: A Role for Hypoxia-Inducible Factor-1? Mol. Cancer Res., February 1, 2003; 1(4): 312 - 322. [Abstract] [Full Text] [PDF]
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 R. M. Adam, J. Kim, J. Lin, A. Orsola, L. Zhuang, D. C. Rice, and M. R. Freeman* Heparin-Binding Epidermal Growth Factor-Like Growth Factor Stimulates Androgen-Independent Prostate Tumor Growth and Antagonizes Androgen Receptor Function Endocrinology, December 1, 2002; 143(12): 4599 - 4608. [Abstract] [Full Text] [PDF]
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Y.-F. Lee, W.-J. Lin, J. Huang, E. M. Messing, F. L. Chan, G. Wilding, and C. Chang Activation of Mitogen-activated Protein Kinase Pathway by the Antiandrogen Hydroxyflutamide in Androgen Receptor-negative Prostate Cancer Cells Cancer Res., November 1, 2002; 62(21): 6039 - 6044. [Abstract] [Full Text] [PDF]
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C. Agarwal, R. P. Singh, and R. Agarwal Grape seed extract induces apoptotic death of human prostate carcinoma DU145 cells via caspases activation accompanied by dissipation of mitochondrial membrane potential and cytochrome c release Carcinogenesis, November 1, 2002; 23(11): 1869 - 1876. [Abstract] [Full Text] [PDF]
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T. Ueda, N. R. Mawji, N. Bruchovsky, and M. D. Sadar Ligand-independent Activation of the Androgen Receptor by Interleukin-6 and the Role of Steroid Receptor Coactivator-1 in Prostate Cancer Cells J. Biol. Chem., October 4, 2002; 277(41): 38087 - 38094. [Abstract] [Full Text] [PDF]
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I. K. Mellinghoff, C. Tran, and C. L. Sawyers Growth Inhibitory Effects of the Dual ErbB1/ErbB2 Tyrosine Kinase Inhibitor PKI-166 on Human Prostate Cancer Xenografts Cancer Res., September 15, 2002; 62(18): 5254 - 5259. [Abstract] [Full Text] [PDF]
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D. Gioeli, S. B. Ficarro, J. J. Kwiek, D. Aaronson, M. Hancock, A. D. Catling, F. M. White, R. E. Christian, R. E. Settlage, J. Shabanowitz, et al. Androgen Receptor Phosphorylation. REGULATION AND IDENTIFICATION OF THE PHOSPHORYLATION SITES J. Biol. Chem., August 2, 2002; 277(32): 29304 - 29314. [Abstract] [Full Text] [PDF]
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J. Dai, R. Shen, M. Sumitomo, R. Stahl, D. Navarro, M. C. Gershengorn, and D. M. Nanus Synergistic Activation of the Androgen Receptor by Bombesin and Low-Dose Androgen Clin. Cancer Res., July 1, 2002; 8(7): 2399 - 2405. [Abstract] [Full Text] [PDF]
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J. Milanini-Mongiat, J. Pouyssegur, and G. Pages Identification of Two Sp1 Phosphorylation Sites for p42/p44 Mitogen-activated Protein Kinases. THEIR IMPLICATION IN VASCULAR ENDOTHELIAL GROWTH FACTOR GENE TRANSCRIPTION J. Biol. Chem., May 31, 2002; 277(23): 20631 - 20639. [Abstract] [Full Text] [PDF]
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T. Karashima, P. Sweeney, J. W. Slaton, S. J. Kim, D. Kedar, J. I. Izawa, Z. Fan, C. Pettaway, D. J. Hicklin, T. Shuin, et al. Inhibition of Angiogenesis by the Antiepidermal Growth Factor Receptor Antibody ImClone C225 in Androgen-independent Prostate Cancer Growing Orthotopically in Nude Mice Clin. Cancer Res., May 1, 2002; 8(5): 1253 - 1264. [Abstract] [Full Text] [PDF]
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S. N. Malik, M. Brattain, P. M. Ghosh, D. A. Troyer, T. Prihoda, R. Bedolla, and J. I. Kreisberg Immunohistochemical Demonstration of Phospho-Akt in High Gleason Grade Prostate Cancer Clin. Cancer Res., April 1, 2002; 8(4): 1168 - 1171. [Abstract] [Full Text] [PDF]
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T. Ueda, N. Bruchovsky, and M. D. Sadar Activation of the Androgen Receptor N-terminal Domain by Interleukin-6 via MAPK and STAT3 Signal Transduction Pathways J. Biol. Chem., February 22, 2002; 277(9): 7076 - 7085. [Abstract] [Full Text] [PDF]
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C. Tognon, M. Garnett, E. Kenward, R. Kay, K. Morrison, and P. H. B. Sorensen The Chimeric Protein Tyrosine Kinase ETV6-NTRK3 Requires both Ras-Erk1/2 and PI3-Kinase-Akt Signaling for Fibroblast Transformation Cancer Res., December 1, 2001; 61(24): 8909 - 8916. [Abstract] [Full Text] [PDF]
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J. R. Graff, B. W. Konicek, J. A. Deddens, M. Chedid, B. M. Hurst, B. Colligan, B. L. Neubauer, H. W. Carter, and J. H. Carter Expression of Group IIa Secretory Phospholipase A2 Increases with Prostate Tumor Grade Clin. Cancer Res., December 1, 2001; 7(12): 3857 - 3861. [Abstract] [Full Text] [PDF]
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H. Murillo, L. J. Schmidt, and D. J. Tindall Tyrphostin AG825 Triggers p38 Mitogen-activated Protein Kinase-dependent Apoptosis in Androgen-independent Prostate Cancer Cells C4 and C4-2 Cancer Res., October 1, 2001; 61(20): 7408 - 7412. [Abstract] [Full Text] [PDF]
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J. Albanell, J. Codony-Servat, F. Rojo, J. M. Del Campo, S. Sauleda, J. Anido, G. Raspall, J. Giralt, J. Rosello, R. I. Nicholson, et al. Activated Extracellular Signal-regulated Kinases: Association with Epidermal Growth Factor Receptor/Transforming Growth Factor {alpha} Expression in Head and Neck Squamous Carcinoma and Inhibition by Anti-Epidermal Growth Factor Receptor Treatments Cancer Res., September 1, 2001; 61(17): 6500 - 6510. [Abstract] [Full Text] [PDF]
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N. Segawa, M. Nakamura, Y. Nakamura, I. Mori, Y. Katsuoka, and K. Kakudo Phosphorylation of Mitogen-activated Protein Kinase is Inhibited by Calcitonin in DU145 Prostate Cancer Cells Cancer Res., August 1, 2001; 61(16): 6060 - 6063. [Abstract] [Full Text] [PDF]
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M. Sun, G. Wang, J. E. Paciga, R. I. Feldman, Z.-Q. Yuan, X.-L. Ma, S. A. Shelley, R. Jove, P. N. Tsichlis, S. V. Nicosia, et al. AKT1/PKB{alpha} Kinase Is Frequently Elevated in Human Cancers and Its Constitutive Activation Is Required for Oncogenic Transformation in NIH3T3 Cells Am. J. Pathol., August 1, 2001; 159(2): 431 - 437. [Abstract] [Full Text]
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 S. Signoretti, R. Montironi, J. Manola, A. Altimari, C. Tam, G. Bubley, S. Balk, G. Thomas, I. Kaplan, L. Hlatky, et al. Her-2-neu Expression and Progression Toward Androgen Independence in Human Prostate Cancer J Natl Cancer Inst, December 6, 2000; 92(23): 1918 - 1925. [Abstract] [Full Text] [PDF]
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X. Zi, R. P. Singh, and R. Agarwal Impairment of erbB1 receptor and fluid-phase endocytosis and associated mitogenic signaling by inositol hexaphosphate in human prostate carcinoma DU145 cells Carcinogenesis, December 1, 2000; 21(12): 2225 - 2235. [Abstract] [Full Text] [PDF]
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E. A. Sheta, M. A. Harding, M. R. Conaway, and D. Theodorescu Focal Adhesion Kinase, Rap1, and Transcriptional Induction of Vascular Endothelial Growth Factor J Natl Cancer Inst, July 5, 2000; 92(13): 1065 - 1073. [Abstract] [Full Text] [PDF]
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T. M. Moore, R. Garg, C. Johnson, M. J. Coptcoat, A. J. Ridley, and J. D. H. Morris PSK, a Novel STE20-like Kinase Derived from Prostatic Carcinoma That Activates the c-Jun N-terminal Kinase Mitogen-activated Protein Kinase Pathway and Regulates Actin Cytoskeletal Organization J. Biol. Chem., February 11, 2000; 275(6): 4311 - 4322. [Abstract] [Full Text] [PDF]
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W.-S. Shim, M. Conaway, S. Masamura, W. Yue, J.-P. Wang, R. Kumar, and R. J. Santen Estradiol Hypersensitivity and Mitogen-Activated Protein Kinase Expression in Long-Term Estrogen Deprived Human Breast Cancer Cells in Vivo Endocrinology, January 1, 2000; 141(1): 396 - 405. [Abstract] [Full Text] [PDF]
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N. Craft, C. Chhor, C. Tran, A. Belldegrun, J. DeKernion, O. N. Witte, J. Said, R. E. Reiter, and C. L. Sawyers Evidence for Clonal Outgrowth of Androgen-independent Prostate Cancer Cells from Androgen-dependent Tumors through a Two-Step Process Cancer Res., October 1, 1999; 59(19): 5030 - 5036. [Abstract] [Full Text] [PDF]
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D. Ye, J. Mendelsohn, and Z. Fan Androgen and Epidermal Growth Factor Down-Regulate Cyclin-dependent Kinase Inhibitor p27Kip1 and Costimulate Proliferation of MDA PCa 2a and MDA PCa 2b Prostate Cancer Cells Clin. Cancer Res., August 1, 1999; 5(8): 2171 - 2177. [Abstract] [Full Text] [PDF]
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J. R. Graff, B. W. Konicek, A. M. McNulty, Z. Wang, K. Houck, S. Allen, J. D. Paul, A. Hbaiu, R. G. Goode, G. E. Sandusky, et al. Increased AKT Activity Contributes to Prostate Cancer Progression by Dramatically Accelerating Prostate Tumor Growth and Diminishing p27Kip1 Expression J. Biol. Chem., August 4, 2000; 275(32): 24500 - 24505. [Abstract] [Full Text] [PDF]
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R. Hoshino, S. Tanimura, K. Watanabe, T. Kataoka, and M. Kohno Blockade of the Extracellular Signal-regulated Kinase Pathway Induces Marked G1 Cell Cycle Arrest and Apoptosis in Tumor Cells in Which the Pathway Is Constitutively Activated. UP-REGULATION OF p27Kip1 J. Biol. Chem., January 19, 2001; 276(4): 2686 - 2692. [Abstract] [Full Text] [PDF]
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E. Mueller, M. Smith, P. Sarraf, T. Kroll, A. Aiyer, D. S. Kaufman, W. Oh, G. Demetri, W. D. Figg, X.-P. Zhou, et al. Effects of ligand activation of peroxisome proliferator-activated receptor gamma in human prostate cancer PNAS, September 26, 2000; 97(20): 10990 - 10995. [Abstract] [Full Text] [PDF]
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