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Query: UMLS:C0005684 (bladder cancer)
 16,431 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The extracellular microenvironment of tumors differs from that of most normal tissues. Many tumors have relatively acidic extracellular pH, although the intracellular pH of tumor cells remains normal due to the efficient maintenance of a large proton gradient across the membrane. This difference between tumors and normal tissues might be exploited therapeutically by disruption of the mechanisms that regulate intracellular pH, so that tumor cells are killed by intracellular acid-induced injury. To investigate the mechanisms by which intracellular acidification leads to cell death, we have studied the roles of the antiapoptotic gene bcl-2 and its proapoptotic binding partner bax, the stress-activated protein kinases (SAPK/JNK), and the caspase proteases in mediating acid-induced cell death. Whereas the expression of bcl-2 in human bladder cancer MGH-U1 cells had no effect on acid-induced death, overexpression of bax enhanced cell death, consistent with its proapoptotic function. Inhibition of SAPK, through the expression of a dominant negative mutant of its activator, SEK1, protected cells from acid-induced cell death. Caspase activation, as measured by poly(ADP-ribose) polymerase cleavage, was absent after lethal intracellular acidification. Consistent with this observation, inhibition of interleukin 1beta-converting enzyme proteases by the peptide z-Val-Ala-Asp(OMe)-CH2F did not protect against acid-induced cell killing. We conclude that acid-induced cell death depends on bax and on SAPK signaling pathways, but not on the caspase proteases. Therapeutic manipulation of bax and SAPK may enhance acid-induced tumor cell killing.
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PMID:Death of tumor cells after intracellular acidification is dependent on stress-activated protein kinases (SAPK/JNK) pathway activation and cannot be inhibited by Bcl-2 expression or interleukin 1beta-converting enzyme inhibition. 966 94

The extracellular microenvironment of tumors differs from most normal tissues. Many tumors have relatively acidic extracellular pH (pHe), although the intracellular pH (pHi) of tumor cells remains normal due to efficient maintenance of a large proton gradient across the membrane. This difference between tumors and normal tissues might be exploited therapeutically by disruption of the mechanisms which regulate pHi, so that tumor cells are killed by intracellular acid-induced injury. To investigate the mechanisms by which intracellular acidification leads to cell death, we have studied the roles of the anti-apoptotic gene bcl-2 and its pro-apoptotic binding partner bax, the Stress Activated Protein Kinases (SAPK/JNK), and the caspase proteases in mediating acid-induced cell death. While expression of bcl-2 in human bladder cancer MGH-U1 cells had no effect on acid-induced death, overexpression of bax enhanced cell death, consistent with its pro-apoptotic function. Inhibition of SAPK, through expression of a dominant negative mutant of its activator, SEK1 protected cells from acid-induced cell death. Caspase activation, as measured by poly (ADP-ribose) polymerase cleavage, was absent after lethal intracellular acidification. Consistent with this observation, inhibition of ICE proteases by the peptide z-VAD.fmk did not protect against acid-induced cell killing. We conclude that acid-induced cell death depends on bax and on SAPK signaling pathways but not on the caspase proteases. Therapeutic manipulation of bax and SAPK may enhance acid-induced tumor cell killing.
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PMID:Inhibition of apoptotic signaling pathways in cancer cells as a mechanism of chemotherapy resistance. 977 Jan 20

Signalling through G-protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTK) is involved in the regulation of essential cellular processes and its deregulation is associated with tumorigenesis in vitro and in vivo. We investigated pathophysiological processes that are regulated by GPCR pathways in human kidney and bladder cancer cell lines. Our results show that GPCR ligands induce tyrosine phosphorylation of the epidermal growth factor receptor (EGFR) as well as downstream signalling events such as recruitment of the adapter protein Shc and activation of the mitogen-activated protein kinases (MAPK) ERK1/2, JNK and p38. Moreover, we report that the EGFR transactivation signal involves the EGFR ligands amphiregulin, HB-EGF and TGFalpha as well as the metalloproteinases ADAM 10, 15 and 17, depending on the cellular system. Finally, we demonstrate that EGFR transactivation is part of a regulatory system that modulates the migratory and invasive behaviour of kidney and bladder cancer cells. In conclusion, our findings demonstrate that metalloproteinase-mediated transactivation of the EGFR is a key mechanism of the cellular signalling network that promotes MAPK activation as well as tumour cell migration and invasion in response to a variety of physiologically relevant GPCR ligands, and therefore represents a novel target for cancer intervention strategies.
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PMID:Multiple G-protein-coupled receptor signals converge on the epidermal growth factor receptor to promote migration and invasion. 1464 23

To improve chemotherapeutic efficacy in urothelial cancer, it is important to identify predictive markers for chemosensitivity as well as possible molecules accelerating cell killing mechanisms. In this study, we assessed the possibility of galectin-7 to accelerate cis-diamminedichloroplatinum (CDDP)-induced cell killing in vitro and also to predict chemosensitivity against CDDP in urothelial cancer patients. The expression of galectin-7 was analyzed in five bladder cancer cell lines with different p53 status after treatment with CDDP. The roles of galectin-7 in chemosensitivity against CDDP were analyzed by transfection of the galectin-7 gene into several of these cell lines. Furthermore, the relationship between the expression of galectin-7 and the response to neoadjuvant chemotherapy was analyzed in 17 human bladder cancer specimens. Exposure to CDDP induced galectin-7 in cell lines with wild-type p53 but not in those with mutated p53. When the galectin-7 gene was transfected into cell lines with mutated p53, the sensitivity to CDDP increased compared with control transfectants. In addition, galectin-7-transfected cells exhibited more accumulation of intracellular reactive oxygen species and activation of c-Jun NH(2)-terminal kinase (JNK) and Bax than control transfectants. SP600125, an inhibitor of JNK, or antioxidant N-acetyl-L-cysteine inhibited the enhancement of chemosensitivity against CDDP by galectin-7 transfection. In clinical samples, the expression levels of galectin-7 were significantly lower in urothelial carcinomas compared with normal urothelium. When chemosensitivity was tested, its expression levels were higher in the chemosensitive group than in the chemoresistant group. Galectin-7 is a candidate for a predictive marker of chemosensitivity against CDDP, and the targeted expression of galectin-7 might overcome the chemoresistance of urothelial cancer.
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PMID:Sensitizing effect of galectin-7 in urothelial cancer to cisplatin through the accumulation of intracellular reactive oxygen species. 1728 57

Magnolia officinalis is a commonly used herb in East Asian countries and has multiple pharmacological effects. Although Magnolia officinalis has a variety of pharmacological effects on certain cancer cell types, the molecular mechanisms on urinary bladder cancer are unclear. An aqueous extract of M. officinalis inhibited cell proliferation in cultured human urinary bladder cancer 5637 cells. Inhibition of proliferation was associated with G1 cell cycle arrest. Treatment with M. officinalis extract blocked the cell cycle in the G1 phase, down-regulated the expression of cyclins and CDKs and up-regulated the expressions of p21WAF1 and p27 Kip1, which are CDK inhibitors. In addition, M. officinalis extract induced a marked activation of p38 MAP kinase and JNK. SB203580, a p38 MAP kinase specific inhibitor, blocked the expression of M. officinalis extract-dependent p38 MAP kinase and p21WAF1. Blockage of the p38 MAPK kinase function reversed M. officinalis extract-induced cell proliferation. These data demonstrate that M. officinalis extract-induced cell growth inhibition appears to be linked to the activation of p38 MAP kinase through p21WAF1 expression. Moreover, treatment of 5637 cells with M. officinalis extract suppressed constitutive and TNF-alpha-induced-nuclear factor-kappa B (NF-kappaB) activation. Furthermore, the transactivation of TNF-alpha-stimulated NF-kappaB was inhibited by SB203580 treatment. Collectively, these results suggest that the p38 MAP kinase pathway contributes, at least partially, to the anti-cancer activity of M. officinalis extract in human urinary bladder tumor 5637 cells.
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PMID:Aqueous extract of Magnolia officinalis mediates proliferative capacity, p21WAF1 expression and TNF-alpha-induced NF-kappaB activity in human urinary bladder cancer 5637 cells; involvement of p38 MAP kinase. 1767 27

The expression of matrix metalloproteinase-9 (MMP-9) has been implicated in tumor invasion and metastasis. In this study, the factors and signaling pathways that are involved in the regulation of the MMP-9 expression were examined in urinary bladder cancer HT1376 cells. Tumor necrosis factor-alpha (TNF-alpha) stimulated the secretion of MMP-9 in HT1376 cells, as shown by zymography and immunoblot analysis. At the level of transcription, TNF-alpha also stimulated 5'-flanking promoter activity of MMP-9. Transcription factor NF-kappaB, AP-1 and Sp-1 binding sites were identified by a gel shift assay to be cis-elements for TNF-alpha activation of the MMP-9 promoter. TNF-alpha activates multiple signaling pathways in HT1376 cells, including the extracellular signal-regulated kinase (ERK1/2), p38 MAP kinase and JNK pathways. Chemical inhibitors, which specifically inhibit each of these TNF-alpha-activated pathways, were used to examine the signaling pathways involved in TNF-alpha-mediated MMP-9 expression. The ERK1/2 inhibitor, U0126 and the p38 MAP kinase inhibitor, SB203580, significantly down-regulated TNF-alpha-induced MMP-9 expression and promoter activity. The transactivation of TNF-alpha-stimulated NF-kappaB, AP-1 and Sp-1 were inhibited by U0126 and SB203580 treatment. In conclusion, the findings of the present study indicate that TNF-alpha induces MMP-9 expression in HT1376 cells by activating transcription factors, which are involved in the ERK1/2- and p38 MAP kinase-mediated control of MMP-9 regulation, namely, NF-kappaB, AP-1 and Sp-1.
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PMID:Activation of matrix metalloproteinase-9 by TNF-alpha in human urinary bladder cancer HT1376 cells: the role of MAP kinase signaling pathways. 1835 89

Magnolol has been reported to play a role in antitumor activity. However, the relevant pathway integrating cell cycle regulation and signaling pathways involved in growth inhibition in cancer cells remains to be identified. In the present study, magnolol treatment of these cells resulted in significant dose-dependent growth inhibition together with apoptosis, G1- and G2/M-phase cell cycle arrest at a 60 microM (IC50) dose in 5637 bladder cancer cells. In addition, magnolol treatment strongly induced p27KIP1 expression, and down-regulated expression of cyclin-dependent kinases (CDKs) and cyclins. Moreover, treatment with magnolol-induced phosphorylation of ERK, p38 MAP kinase, and JNK. Among the pathway inhibitors examined, only PD98059, an ERK-specific inhibitor, blocked magnolol-dependent p27KIP1 expression. Blockade of ERK function consistently reversed magnolol-mediated inhibition of cell proliferation and decreased G2/M cell cycle proteins, but not G1 cell cycle proteins. Furthermore, magnolol treatment increased both Ras and Raf activation. Transfection of cells with dominant negative Ras (RasN17) and Raf (RafS621A) mutant genes suppressed magnolol-induced ERK activity and p27KIP1 expression. Finally, the magnolol-induced reduction in cell proliferation and G2/M cell cycle proteins was also abolished in the presence of RasN17 and RafS621A mutant genes. These data demonstrate that the Ras/Raf/ERK pathway participates in p27KIP1 induction, leading to a decrease in the levels of cyclin B1/Cdc2 complexes and magnolol-dependent inhibition of cell growth. Overall, these novel findings concerning the molecular mechanisms of magnolol in 5637 bladder cancer cells provide a theoretical basis for therapeutic treatment of malignancies.
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PMID:Magnolol elicits activation of the extracellular signal-regulated kinase pathway by inducing p27KIP1-mediated G2/M-phase cell cycle arrest in human urinary bladder cancer 5637 cells. 1846 78

TLR4 (Toll-like receptor 4) and B7-H1, which were known to be restricted to immune cells in the past, were found to be aberrantly expressed in a majority of tumor cells, facilitating tumor evasion from immune surveillance. Our study demonstrated that activation of TLR4 signaling in bladder cancer cells up-regulated B7-H1 expression. Furthermore, this regulation was significantly attenuated by ERK or JNK inhibitor. Our results elucidated the molecule mechanism of regulation of B7-H1 expression through TLR4 signaling and may suggest new strategies of down-regulating the cancer-associated B7-H1 expression for bladder cancer treatment.
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PMID:TLR4 signaling induces B7-H1 expression through MAPK pathways in bladder cancer cells. 1860 6

We have recently shown that a new therapeutic modality using the REIC/Dkk-3 gene (Ad-REIC) is effective against various human cancers, including those of prostate, testis and breast origins. The aim of the present study was to examine the sensitivity of bladder cancers to Ad-REIC and to clarify the molecular mechanisms that determine sensitivity/resistance. We found that 2 human bladder cancer cell lines, T24 and J82, are resistant to Ad-REIC. In T24 and J82 cells, the ER stress response and activation of JNK were observed in a manner similar to that in the sensitive PC3 cells. Translocation of Bax to mitochondria occurred in PC3 cells but not in T24 and J82 cells. Bcl-2 was remarkably overexpressed in T24 and J82 compared with the expression levels in sensitive cell lines. Treatment of T24 and J82 cells with a Bcl-2 inhibitor sensitized the cells to Ad-REIC-induced apoptosis. The results indicate that some human bladder cancers are resistant to apoptosis induced by overexpression of REIC/Dkk-3, which is at least in part due to up-regulation of Bcl-2. These results provide a basis for possible use of Bcl-2 as a marker of sensitive cancers and to try to sensitize resistant cancers to Ad-REIC by down-regulation of Bcl-2.
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PMID:Mechanistic analysis of resistance to REIC/Dkk-3-induced apoptosis in human bladder cancer cells. 1912 85

We recently identified a novel human AlkB homologue, ALKBH8, which is expressed in various types of human cancers including human urothelial carcinomas. In examining the role and function of ALKBH8 in human bladder cancer development in vitro, we found that silencing of ALKBH8 through small interfering RNA transfection reduced reactive oxygen species (ROS) production via down-regulation of NAD(P)H oxidase-1 (NOX-1) and induced apoptosis through subsequent activation of c-jun NH(2)-terminal kinase (JNK) and p38. However, we also found that JNK and p38 activation resulted in phosphorylation of H2AX (gammaH2AX), a variant of mammalian histone H2A, which contributes to the apoptosis induced by silencing ALKBH8 and NOX-1. Silencing of ALKBH8 significantly suppressed invasion, angiogenesis, and growth of bladder cancers in vivo as assessed both in the chorioallantoic membrane assay and in an orthotopic mouse model using green fluorescent protein-labeled KU7 human urothelial carcinoma cells. Immunohistochemical examination showed high expression of ALKBH8 and NOX-1 proteins in high-grade, superficially and deeply invasive carcinomas (pT(1) and >pT(2)) as well as in carcinoma in situ, but not in low-grade and noninvasive phenotypes (pT(a)). These findings indicate an essential role for ALKBH8 in urothelial carcinoma cell survival mediated by NOX-1-dependent ROS signals, further suggesting new therapeutic strategies in human bladder cancer by inducing JNK/p38/gammaH2AX-mediated cell death by silencing of ALKBH8.
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PMID:A novel human AlkB homologue, ALKBH8, contributes to human bladder cancer progression. 1929 82


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