Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bcl-2 overexpression is an important mechanism underlying the aggressive behavior of prostate cancer cells and their resistance to radio- or chemotherapy. HA14-1, a recently discovered organic Bcl-2 inhibitor, potently induces apoptosis in various human cancer cells. Sequential exposure of radioresistant LNCaP (wild-type (wt) p53), LNCaP/Bcl-2 (wt p53) and PC3 (mutant p53) prostate cancer cells to a minimally cytotoxic concentration of 10 microM HA14-1 for 1 h followed by 1-6 Gy gamma radiation, resulted in a highly synergistic (combination index <1.0) induction of cell death as determined by an apoptosis assay at 72 h, and a clonogenicity assay at 12 days, after the initial treatment. The reverse treatment sequence did not cause a synergistic induction of cell death. When compared to individual treatments, cell death induced by the combined treatment was associated with dramatically increased reactive oxygen species (ROS) generation, c-Jun N-terminal kinase (JNK) activation, Bcl-2 phosphorylation, cytochrome c release, caspase-3 activation and DNA fragmentation. Exposure to either 200 microg/ml of the antioxidant alpha-tocopherol or 10 microM JNK inhibitor SP600125 before the combined treatment resulted in decreased activation of JNK and caspase-3 as well as decreased DNA fragmentation. However, treatment with the pancaspase inhibitor carbobenzoxyl-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone before the combined treatment inhibited apoptosis without affecting JNK activation, and this inhibitory effect was enhanced in the presence of alpha-tocopherol or SP600125. Taken together, our results indicate that HA14-1 potently sensitizes radioresistant LNCaP and PC3 cells to gamma radiation, regardless of the status of p53. ROS and JNK are important early signals that trigger both caspase-dependent and -independent cell death pathways and contribute to the apoptotic synergy induced by the combined treatments.
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PMID:Overcoming the radioresistance of prostate cancer cells with a novel Bcl-2 inhibitor. 1690 21

In last couple of decades the use of natural compounds like flavonoids as chemopreventive agents has gained much attention. Our current study focuses on identifying chemopreventive flavonoids and their mechanism of action on human prostate cancer cells. Human prostate cancer cells (PC3), stably transfected with activator protein 1 (AP-1) luciferase reporter gene were treated with four main classes of flavonoids namely flavonols, flavones, flavonones, and isoflavones. The maximum AP-1 luciferase induction of about 3 fold over control was observed with 20 microM concentrations of quercetin, chrysin and genistein and 50 microM concentration of kaempferol. At higher concentrations, most of the flavonoids demonstrated inhibition of AP-1 activity. The MTS assay for cell viability at 24 h showed that even at a very high concentration (500 microM), cell death was minimal for most of the flavonoids. To determine the role of MAPK pathway in the induction of AP-1 by flavonoids, Western blot of phospho MAPK proteins was performed. Four out of the eight flavonoids namely kaempferol, apigenin, genistein and naringenin were used for the Western Blot analysis. Induction of phospho-JNK and phospho-ERK activity was observed after two hour incubation of PC3-AP1 cells with flavonoids. However no induction of phospho-p38 activity was observed. Furthermore, pretreating the cells with specific inhibitors of JNK reduced the AP-1 luciferase activity that was induced by genistein while pretreatment with MEK inhibitor reduced the AP-1 luciferase activity induced by kaempferol. The pharmacological inhibitors did not affect the AP-1 luciferase activity induced by apigenin and naringenin. These results suggest the possible involvement of JNK pathway in genistein induced AP-1 activity while the ERK pathway seems to play an important role in kaempferol induced AP-1 activity.
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PMID:Modulation of activator protein-1 (AP-1) and MAPK pathway by flavonoids in human prostate cancer PC3 cells. 1696 58

During its biological progression, prostate cancer frequently develops dependence on growth factor receptors and their downstream signalling messengers, including c-Src. Evidence for this supports the choice of c-Src as a therapeutic target in the prevention of tumour spreading. Two new pyrazolo[3,4-d]pyrimidines c-Src inhibitors, SI35 and SI40, were used to investigate the role of c-Src in the control of the aggressive phenotype of prostate carcinoma cell line, PC3. SI molecules reduced the proliferation of PC3 cells in a time- and dose-dependent manner, with an IC50 of approximately 50 microM. PC3 cells responded to the presence of epidermal growth factor (EGF) by increasing their migratory ability, and this effect was strongly reduced by the addition of SI at concentrations less than IC50. Further observations demonstrated that SI molecules modulated cell morphology and their adhesive capacity on different physiological substrates. The action of SI molecules appeared to involve, in parallel with c-Src inhibition, the down-modulation of the active forms of paxillin and extracellular signal-regulated kinase (ERK). Our data suggest a promising role for pyrazolo[3,4-d]pyrimidines c-Src inhibitors in the control of a highly invasive tumour phenotype.
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PMID:Pyrazolo[3,4-d]pyrimidines c-Src inhibitors reduce epidermal growth factor-induced migration in prostate cancer cells. 1697 47

We have recently shown that the expression levels of both cannabinoid receptors CB(1) and CB(2) are higher in human prostate cancer cells than in normal prostate epithelial cells, and treatment of LNCaP cells with WIN-55,212-2 (a mixed CB(1)/CB(2) agonist) resulted in inhibition of cell growth and induction of apoptosis (Sarfaraz, S., Afaq, F., Adhami, V. M., and Mukhtar, H. (2005) Cancer Res. 65, 1635-1641). This study was conducted to understand the mechanistic basis of these effects. Treatment of LNCaP cells with WIN-55,212-2 (1-10 microm; 24 h) resulted in: (i) an arrest of the cells in the G(0)/G(1) phase of the cell cycle; (ii) an induction of p53 and p27/KIP1; (iii) down-regulation of cyclins D1, D2, E; (iii) decrease in the expression of cdk-2, -4, and -6; (iv) decrease in protein expression of pRb; (v) down-regulation of E2F (1-4); and (vi) decrease in the protein expression of DP1 and DP2. Similar effects were also observed when androgen-independent PC3 cells were treated with WIN-55,212-2 (5-30 microm). We further observed sustained up-regulation of ERK1/2 and inhibition of PI3k/Akt pathways in WIN-55,212-2-treated cells. Inhibition of ERK1/2 abrogated WIN-55,212-2-indued cell death suggesting that sustained activation of ERK1/2 leads to cell cycle dysregulation and arrest of cells in G(0)/G(1) phase subsequently leading to an induction of apoptosis. Further, WIN-55,212-2 treatment of cells resulted in a dose-dependent increase in Bax/Bcl-2 ratio in such a way that favors apoptosis. The induction of apoptosis proceeded through down-regulation of caspases 3, 6, 7, and 9 and cleavage of poly (ADP-ribose) polymerases. Based on these data we suggest that cannabinoid receptor agonists should be considered as novel agents for the management of prostate cancer.
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PMID:Cannabinoid receptor agonist-induced apoptosis of human prostate cancer cells LNCaP proceeds through sustained activation of ERK1/2 leading to G1 cell cycle arrest. 1706 43

In this paper, we will outline the current understanding of cell cycle modulation and induction of apoptosis in cancer cells by natural and synthetic bile acid. Bile acid homeostasis is tightly regulated in health, and their cellular and tissue concentrations are restricted. However, when pathophysiological processes impair their biliary secretion, hepatocytes are exposed to elevated concentrations of bile acids which trigger cell death. In this context, we developed several newly synthesized bile acid derivatives. These synthetic bile acids modulated the cell cycle and induced apoptosis in several human cancer cells similar to natural bile acids. In human breast and prostate cancer cells with different tumor suppressor p53 status, synthetic bile acid-induced growth inhibition and apoptosis were associated with up-regulation of Bax and p21(WAF1/CIP1) via a p53-independent pathway. In Jurkat human T cell leukemia cells, the synthetic bile acids induced apoptosis through caspase activation. In addition to this, the synthetic bile acids induced apoptosis in a JNK dependent manner in SiHa human cervical cancer cells, via induction of Bax and activation of caspases in PC3 prostate cancer cells and induction of G1 phase arrest in the cell cycle in HT29 colon cancer cells. Moreover, they induced apoptosis in four human glioblastoma multiform cell lines (i.e., U-118MG, U-87MG, T98G, and U-373MG) and one human TE671 medulloblastoma cells. In addition to this, a chenodeoxycholic acid derivative, called HS-1200, significantly decreased the growth of TE671 medulloblastoma tumor size and increased life span in non-obese diabetic and severe combined immunodeficient (NOD/SCID) mice. Therefore, these new synthetic bile acids, which are novel apoptosis mediators, might be applicable to the treatment of various human cancer cells.
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PMID:Modulation of the cell cycle and induction of apoptosis in human cancer cells by synthetic bile acids. 1716 73

Activation of mitogen/extracellular-signal-regulated kinase kinase 5/extracellular signal-regulated kinase-5 (MEK5/ERK5) growth signalling is coupled to increased cell proliferation in prostate cancer (PCa). Dysregulation of the DNA replication licensing pathway, a critical step in growth control downstream of transduction signalling pathways, is associated with development of PCa. In this study we have investigated linkages between the MEK5/ERK5 pathway and DNA replication licensing during prostate carcinogenesis. The effects of increased MEK5/ERK5 signalling on the expression of replication licensing factors Mcm2 and geminin and the proliferation marker Ki67 were studied in an ecdysone-inducible system expressing a constitutively activated mutant of MEK5 in EcR293 cells and in stable ERK5 over-expressing PC3 clones. In parallel, expression of these biomarkers in PCa biopsy specimens (n=58) was studied and compared to clinicopathological parameters. In both in vitro systems induction of MEK5 expression resulted in increased levels of phosphorylated ERK5 and Mcm2, geminin and Ki67 proteins. In PCa specimens average Mcm2 expression was greater than Ki67 and geminin expression (median labelling index (LI) 36.7, 18.1, and 3.4% respectively), consistent with their differential expression according to growth status (P<0.0001). Mcm2, geminin and Ki67 expression were significantly associated with Gleason grade (P=0.0002, P=0.0003, P=0.004); however there was no link with T or M stage. There was a significant relationship between increasing ERK5 expression and increasing Mcm2 (P=0.003) and Ki67 (P=0.009) expression, with non-significant trends seen with increasing MEK5 expression. There were significant associations between Gleason grade and the number of cells traversing G1 phase (Ki67(LI)-geminin(LI); (P=0.001)), with high ERK5 levels associated with both an increase in replication licensed but non-cycling cells (Mcm2(LI)-Ki67(LI); (P=0.01)) and accelerated cell cycle progression (geminin(LI)/Ki67(LI); (P= 0.005)), all indicative of a shift towards increasing proliferative potential. While Mcm2 and Ki67 were both prognostic factors on univariate analysis, only Mcm2 remained an independent prognostic marker on multivariate analysis. Taken together, our data show that induction of MEK5/ERK5 signalling is linked to activation of the DNA replication licensing pathway in PCa, and that the strong prognostic value of MCM proteins may result from their function as relay stations coupling growth regulatory pathways to genome duplication.
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PMID:Mitogenic growth signalling, DNA replication licensing, and survival are linked in prostate cancer. 1740 59

Acquisition of androgen independence by prostate cancer is the key problem of prostate cancer progression. Vasoactive intestinal peptide (VIP), a neuropeptide, may act as a survival factor for prostate cancer cells under androgen deprivation. However, the molecular mechanisms by which VIP promotes the androgen-independent growth of androgen-sensitive prostate cancer cells have not been addressed. We therefore investigated the biological effect and signal pathway of VIP in LNCaP cells, a prostate cancer cell line that requires androgens for growth. We showed that low nanomolar concentrations of VIP, acting through G(s)-protein-coupled VIP receptors, can induce LNCaP cell growth in the absence of androgen. Blockade of androgen-receptor (AR) in these cells by AR antagonist bicalutamide or by anti-AR small interfering RNA, inhibited the proliferative effect of VIP. In addition, VIP stimulated androgen-independent activation of AR with an EC(50) of 3.0 +/- 0.8 nM. We then investigated VIP-stimulated signaling events that may interact with the AR pathway in prostate cancer cells. VIP regulation of AR activation, mediated by VIP receptors, was protein kinase A (PKA)-dependent, and extracellular signal-regulated kinase 1/2 (ERK1/2) activation contributes to VIP-mediated AR activation. Furthermore, PKA-dependent Rap1 activation is required for both ERK1/2 activation and androgen-independent AR activation in LNCaP cells upon VIP stimulation. Finally, we showed that VIP-induced AR activation was also present in prostate cancer CWR22Rv1 and PC3 cells transfected with the wild-type AR. Altogether, we demonstrate that VIP acting through its G(s)-protein-coupled receptors can cause androgen-independent transactivation of AR through a PKA/Rap1/ERK1/2 pathway, thus promoting androgen-independent proliferation of androgen-sensitive prostate cancer cells.
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PMID:Vasoactive intestinal peptide transactivates the androgen receptor through a protein kinase A-dependent extracellular signal-regulated kinase pathway in prostate cancer LNCaP cells. 1743 Sep 95

Prostate cancer cell migration is an essential event both in the progression of prostate cancer and in the steps leading to metastasis. We report here that lysophosphatidic acid (LPA), a potent bioactive phospholipid, induces prostate cancer PC3 cell migration via the activation of the LPA(1) receptor, which is linked to a PTX-sensitive activation mechanism of the mitogen-activated protein kinases (MAPK). Our results demonstrate that parallel activation of ERK1/2 and p38, but not JNK, is responsible for LPA-stimulated PC3 cell migration. Furthermore, using small interfering RNA (siRNA) technology, and overexpressing dominant-negative mutants of p38 MAPK isotypes of alpha, beta, gamma and delta, we have identified that the activation of ERK2 (p42) and p38alpha, but not of ERK1 and the other isoforms of p38 MAPK, is required for LPA-induced migration. Our study provides the first evidence for a functional role of p42 and p38alpha in LPA-induced mammalian cell migration, and also demonstrates, for the first time, that the receptor LPA(1) mediates prostate cancer cell migration. The results of the present study suggest that LPA, the receptor LPA(1), ERK2 and p38alpha are important regulators for prostate cancer cell invasion and thus could play a significant role in the development of metastasis.
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PMID:Lysophosphatidic acid induces prostate cancer PC3 cell migration via activation of LPA(1), p42 and p38alpha. 1753 30

Podocalyxin is an anti-adhesive transmembrane sialomucin that has been implicated in the development of more aggressive forms of breast and prostate cancer. The mechanism through which podocalyxin increases cancer aggressiveness remains poorly understood but may involve the interaction of podocalyxin with ezrin, an established mediator of metastasis. Here, we show that overexpression of podocalyxin in MCF7 breast cancer and PC3 prostate cancer cell lines increased their in vitro invasive and migratory potential and led to increased expression of matrix metalloproteases 1 and 9 (MMP1 and MMP9). Podocalyxin expression also led to an increase in mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) activity. To determine the role of ezrin in these podocalyxin-dependent phenotypic events, we first confirmed that podocalyxin formed a complex with ezrin in MCF7 and PC3 cells. Furthermore, expression of podocalyxin was associated with a changed ezrin subcellular localization and increased ezrin phosphorylation. Transient knockdown of ezrin protein abrogated MAPK and PI3K signaling as well as MMP expression and invasiveness in cancer cells overexpressing podocalyxin. These findings suggest that podocalyxin leads to increased in vitro migration and invasion, increased MMP expression, and increased activation of MAPK and PI3K activity in MCF7 and PC3 cells through its ability to form a complex with ezrin.
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PMID:Podocalyxin increases the aggressive phenotype of breast and prostate cancer cells in vitro through its interaction with ezrin. 1761 75

Neuroendocrine molecules play a significant role in the progression of human prostate cancer (PCa) and its neuroendocrine differentiation has been associated to a worse prognosis. Evidence exists that, among these molecules, the pleiotropic neuropeptide Y (NPY) and the related receptors may play a role in the normal prostate as well as in the progression of human PCa, which represents one of the most common malignant diseases among men in the Western world. The role of NPY in PCa biology appears to vary in different in vitro human PCa cell systems, since it has been found to reduce the proliferation of LNCaP and DU145 cells, but to stimulate the growth of PC3 cells. These effects are mediated mainly by the NPY Y1 receptor and are associated with a clone-specific pattern of intracellular signaling activation, including a peculiar time-course of MAPK/ERK1/2 phosphorylation (long-lasting in DU145 and transient in PC3 cells). In conclusion, several studies support the concept that NPY and the related receptors are overexpressed in PCa and may play a relevant role in PCa progression. The diagnostic and therapeutical value of targeting the NPY system in PCa will be evaluated in future studies.
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PMID:Modulatory actions of neuropeptide Y on prostate cancer growth: role of MAP kinase/ERK 1/2 activation. 1769 23


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