Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

AMP-activated protein kinase (AMPK) functions as an energy sensor to provide metabolic adaptations under the ATP-deprived conditions such as hypoxia. In the present study, we considered a role of AMPK in the adaptive response to hypoxia by examining whether AMPK is involved in the regulation of hypoxia-inducible factor-1 (HIF-1), a heterodimeric transcription factor that is critical for hypoxic induction of physiologically important genes. We demonstrate that hypoxia or CoCl2 rapidly activated AMPK in DU145 human prostate cancer cells, and its activation preceded the induction of HIF-1 alpha expression. Under these conditions, blockade of AMPK activity by a pharmacological or molecular approach significantly attenuated hypoxia-induced responses such as HIF-1 target gene expression, secretion of vascular endothelial growth factor, glucose uptake, and HIF-1-dependent reporter gene expression, indicating that AMPK is critical for the HIF-1 transcriptional activity and its target gene expression. Its functional requirement for HIF-1 activity was also demonstrated in several different cancer cell lines, but AMPK activation alone was not sufficient to stimulate the HIF-1 transcriptional activity. We further present data showing that AMPK transmits a positive signal for HIF-1 activity via a signaling pathway that is independent of phosphatidylinositol 3-kinase/AKT and several mitogen-activated protein kinases. Taken together, our results suggest that AMPK is a novel and critical component of HIF-1 regulation, implying its new roles in oxygen-regulated cellular phenomena.
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PMID:AMP-activated protein kinase activity is critical for hypoxia-inducible factor-1 transcriptional activity and its target gene expression under hypoxic conditions in DU145 cells. 3044 3

Prostate cancer cells require high rates of de novo fatty acid synthesis and protein synthesis for their rapid growth. We report here that the growth of these cells is markedly diminished by incubation with activators of AMP-activated protein kinase (AMPK), a fuel-sensing enzyme that has been shown to diminish both of these processes in intact tissues. Inhibition of cell growth was observed when AMPK was activated by either 5-aminoimidazole-4-carboxamide riboside (AICAR) or the thiazolidinedione rosiglitazone. Thus, a 90% inhibition of the growth of androgen-independent (DU145, PC3) and androgen-sensitive (LNCaP) cells was achieved after 4 days of exposure to one or both of these agents. Where studied, this was associated with a decrease in the concentration of malonyl CoA, an intermediate of de novo fatty acid synthesis, and an increase in expression of the cell cycle inhibitor p21. In addition, AICAR inhibited two key enzymes involved in protein synthesis, mTOR and p70S6K, and blocked the ability of the androgen R1881 to increase cell growth and the expression of two enzymes for de novo fatty acid synthesis, acetyl CoA carboxylase and fatty acid synthase, in the LNCaP cells. The results suggest that AMPK is a potential target for the treatment of prostate cancer.
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PMID:AMP-activated protein kinase activators can inhibit the growth of prostate cancer cells by multiple mechanisms. 1535 29

Androgen receptor (AR) plays a central role in prostate cancer, with most tumors responding to androgen deprivation therapies, but the molecular basis for this androgen dependence has not been determined. Androgen [5alpha-dihydrotestosterone (DHT)] stimulation of LNCaP prostate cancer cells, which have constitutive phosphatidylinositol 3-kinase (PI3K)/Akt pathway activation due to PTEN loss, caused increased expression of cyclin D1, D2, and D3 proteins, retinoblastoma protein hyperphosphorylation, and cell cycle progression. However, cyclin D1 and D2 message levels were unchanged, indicating that the increases in cyclin D proteins were mediated by a post-transcriptional mechanism. This mechanism was identified as mammalian target of rapamycin (mTOR) activation. DHT treatment increased mTOR activity as assessed by phosphorylation of the downstream targets p70 S6 kinase and 4E-BP1, and mTOR inhibition with rapamycin blocked the DHT-stimulated increase in cyclin D proteins. Significantly, DHT stimulation of mTOR was not mediated through activation of the PI3K/Akt or mitogen-activated protein kinase/p90 ribosomal S6 kinase pathways and subsequent tuberous sclerosis complex 2/tuberin inactivation or by suppression of AMP-activated protein kinase. In contrast, mTOR activation by DHT was dependent on AR-stimulated mRNA synthesis. Oligonucleotide microarrays showed that DHT-stimulated rapid increases in multiple genes that regulate nutrient availability, including transporters for amino acids and other organic ions. These results indicate that a critical function of AR in PTEN-deficient prostate cancer cells is to support the pathologic activation of mTOR, possibly by increasing the expression of proteins that enhance nutrient availability and thereby prevent feedback inhibition of mTOR.
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PMID:Androgens induce prostate cancer cell proliferation through mammalian target of rapamycin activation and post-transcriptional increases in cyclin D proteins. 1688 82

Neurotensin (NT) stimulates the proliferation of prostate cancer PC3 cells, which express high levels of its G protein-coupled receptor NTS1. To shed light on mechanisms that might serve to coordinate mitogenic responses to metabolic status, we studied the effects of metabolic inhibitors on NTS1 function. We also related these effects to cellular ATP levels and to the activation of AMP-activated protein kinase (AMPK). Glycolytic and mitochondrial inhibitors, at concentrations that reduced cellular ATP levels, altered NT binding to the cells, inhibited NT-induced inositol phosphate formation, and inhibited NT-induced DNA synthesis. For eight of the nine inhibitors, the potencies to alter NT receptor function correlated to the potencies to decrease cellular ATP levels. In keeping with its known role to oppose metabolic stress, AMPK was activated by the metabolic inhibitors. Accordingly, the AMPK activator AICAR elevated cellular ATP levels and produced effects on NTS1 function that were opposite to those for the metabolic inhibitors. These results indicate that metabolic stress inhibited NTS1 function by a mechanism that involved a fall in cellular ATP levels and that was opposed by activation of AMPK. In a broader context, these findings are compatible with the idea that one means by which cells might coordinate mitogenic signaling to metabolic status could involve changes in growth factor receptor function.
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PMID:Neurotensin receptor binding and neurotensin-induced growth signaling in prostate cancer PC3 cells are sensitive to metabolic stress. 1728 70

Adiponectin has received much attention due to its beneficial effects on insulin sensitivity, and epidemiologic studies have further shown an inverse association between adiponectin levels and risk for multiple tumors, which is independent of the IGF system or other risk factors. Previous studies have shown that adiponectin can activate AMP-activated protein kinase (AMPK) in myocytes, hepatocytes, and adipocytes, suggesting that adiponectin may suppress tumor development through AMPK activation and subsequent inhibition of mammalian target of rapamycin (mTOR). However, the mechanisms through which adiponectin affects cancer cells are not understood, and it remains to be determined whether adiponectin is linked to the same downstream targets in all cells types, and in particular in cancer cells. In the present study, we demonstrate that while adiponectin stimulates AMPK in phosphatase and tensin homolog deleted on chromosome ten (PTEN) deficient LNCaP prostate cancer cells, it also increases mTOR activity as assessed by phosphorylation of two downstream targets, p70 S6 kinase and ribosomal protein S6. This adiponectin stimulation of mTOR was mediated through phosphatidylinositol 3-kinase (PI3 kinase) and Akt activation. These results show that adiponectin can activate both AMPK and PI3 kinase/Akt pathways, and that cell type-specific factors such as PTEN status may determine which of these pathways will have the dominant effect on mTOR. Therefore, while it is possible that high endogenous adiponectin levels could be protective against cancer by direct mechanisms or indirect systemic mechanisms, our results indicate that adiponectin may also directly stimulate signaling pathways that enhance the growth of some tumors.
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PMID:Adiponectin signals in prostate cancer cells through Akt to activate the mammalian target of rapamycin pathway. 1804 51

Metformin is a widely used antidiabetic agent, which regulates glucose homeostasis through inhibition of liver glucose production and an increase in muscle glucose uptake. Recent studies suggest that metformin may reduce the risk of cancer, but its mode of action in cancer remains not elucidated. We investigated the effect of metformin on human prostate cancer cell proliferation in vitro and in vivo. Metformin inhibited the proliferation of DU145, PC-3 and LNCaP cancer cells with a 50% decrease of cell viability and had a modest effect on normal prostate epithelial cell line P69. Metformin did not induce apoptosis but blocked cell cycle in G(0)/G(1). This blockade was accompanied by a strong decrease of cyclin D1 protein level, pRb phosphorylation and an increase in p27(kip) protein expression. Metformin activated the AMP kinase pathway, a fuel sensor signaling pathway. However, inhibition of the AMPK pathway using siRNA against the two catalytic subunits of AMPK did not prevent the antiproliferative effect of metformin in prostate cancer cells. Importantly, oral and intraperitoneal treatment with metformin led to a 50 and 35% reduction of tumor growth, respectively, in mice bearing xenografts of LNCaP. Similar, to the in vitro study, metformin led to a strong reduction of cyclin D1 protein level in tumors providing evidence for a mechanism that may contribute to the antineoplastic effects of metformin suggested by recent epidemiological studies.
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PMID:The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level. 1821 42

AMP-activated protein kinase (AMPK) serves as a fuel-sensing enzyme that is activated by binding of AMP and subsequent phophorylation by upstream kinases such as the tumor suppressor LKB1, when cells sense an increase in the ratio of AMP to ATP. Acute activation of AMPK stimulates fatty acid oxidation to generate more ATP and simultaneously inhibits ATP-consuming processes including fatty acid and protein syntheses, thereby preserving energy for acute cell-surviving program, whereas chronic activation leads to inhibition of cell growth. The goal of the present study is to explore the mechanisms by which AMPK regulates cell growth. Toward this end, we established stable cell lines by introducing a dominant-negative mutant of AMPK alpha1 subunit or its shRNA into the prostate cancer C4-2 cells and other cells, or wild type LKB1 into the lung adenocarcinoma A549 and breast MB-MDA-231 cancer cells, both of which lack functional LKB1. Our results showed that the inhibition of AMPK accelerated cell proliferation and promoted malignant behavior such as increased cell migration and anchorage-independent growth. This was associated with decreased G1 population, downregulation of p53 and p21, and upregulation of S6K, IGF-1 and IGF1R. Conversely, treatment of the C4-2 cells with 5-aminoimidazole-4-carboxamide 1-D-ribonucleoside (AICAR), a prototypical AMPK activator, caused opposite changes. In addition, our study using microarray and RT-PCR revealed that AMPK regulated gene expression involved in tumor cell growth and survival. Thus, our study provides novel insights into the mechanisms of AMPK action in cancer cells and presents AMPK as an ideal drug target for cancer therapy.
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PMID:Inactivation of AMPK alters gene expression and promotes growth of prostate cancer cells. 1934 29

The molecular mechanisms underlying the development and progression of prostate cancer are poorly understood. AMP-activated protein kinase (AMPK) is a serine-threonine kinase that is activated in response to the hypoxic conditions found in human prostate cancers. In response to energy depletion, AMPK activation promotes metabolic changes to maintain cell proliferation and survival. Here, we report prevalent activation of AMPK in human prostate cancers and provide evidence that inhibition or depletion of AMPK leads to decreased cell proliferation and increased cell death. AMPK was highly activated in 40% of human prostate cancer specimens examined. Endogenous AMPK was active in both the androgen-sensitive LNCaP cells and the androgen-independent CWR22Rv1 human prostate cancer cells. Depletion of AMPK catalytic subunits by small interfering RNA or inhibition of AMPK activity with a small-molecule AMPK inhibitor (compound C) suppresses human prostate cancer cell proliferation. Apoptotic cell death was induced in LNCaP and CWR22Rv1 cells at compound C concentrations that inhibited AMPK activity. The evidence provided here is the first report that the activated AMPK pathway is involved in the growth and survival of human prostate cancer and offers novel potential targets for chemoprevention of human prostate cancer.
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PMID:AMP-activated protein kinase promotes human prostate cancer cell growth and survival. 1937 45

The death receptor Fas (APO-1/CD95) induces apoptosis in many tissues upon cross-linking by its ligand (FasL), but a number of cancer cells exhibit resistance to such apoptosis. Indeed, resistance to apoptosis seems to be one of the hallmarks of cancer, and therefore, it is clinically important to understand the underlying mechanisms by which cancer cells acquire such resistance. In the present study, we demonstrate that Fas signaling in DU145 human prostate cancer cells leads to rapid activation of AMP-activated protein kinase (AMPK), which plays a major role in adaptive responses to ATP-depleting conditions; prostate cancer is resistant to Fas-mediated apoptosis despite high levels of Fas surface expression and no mutation in the Fas gene. We further demonstrate that inhibition of AMPK sensitizes DU145 cells to Fas-induced apoptosis via enhancement of ubiquitination and consequent proteasome degradation of the apoptosis inhibitory protein c-FLIP. These findings thus reveal a novel anticancer property of AMPK inhibition and support the synergistic application of AMPK inhibition in cancer therapy to overcome Fas resistance.
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PMID:Down-regulation of AMP-activated protein kinase sensitizes DU145 carcinoma to Fas-induced apoptosis via c-FLIP degradation. 1947 72

CCL2 is a cytokine prevalent in the prostate cancer tumor microenvironment. Recently, we reported that CCL2 induces the mammalian target of rapamycin (mTOR) pathway to promote prostate cancer PC3 cell survival; however, the mechanism used by CCL2 to maintain mTOR complex-1 (mTORC1) activation requires clarification. This study demonstrates that upon serum starvation, CCL2 functions as a negative regulator of AMP-activated protein kinase (AMPK) by decreasing phosphorylation at its major regulatory site (Thr(172)) in PC3, DU145, and C4-2B prostate cancer cells. The CCL2-mediated AMPK regulation decreased raptor phosphorylation (Ser(792)) resulting in hyperactivation of mTORC1. D942, a pharmacological activator of AMPK, stunted CCL2-induced mTORC1 activity, survivin expression, and cell survival without significantly affecting Akt activity. CCL2, however, conferred some resistance to the lethal effect of D942 compared with untreated cells. By using Akt-specific inhibitor X, it was shown that Akt inactivation did not cause an increase in AMPK phosphorylation in CCL2-stimulated cells, suggesting that CCL2-mediated negative regulation of AMPK is independent of Akt. Furthermore, bisindolylmaleimide-V, a specific inhibitor of p70(S6K), stunted survivin expression and induced cell death in CCL2-treated PC3. Altogether, these findings suggest that CCL2 hyperactivates mTORC1 through simultaneous regulation of both AMPK and Akt pathways and reveals a new network that promotes prostate cancer: CCL2-AMPK-mTORC1-survivin.
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PMID:CCL2 is a negative regulator of AMP-activated protein kinase to sustain mTOR complex-1 activation, survivin expression, and cell survival in human prostate cancer PC3 cells. 2001 39


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