Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0025202 (melanoma)
69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have reported that oridonin isolated from Rabdosia rubescens induces apoptosis of human melanoma A375-S2 cells within 12 h. In this study, TUNEL assay and flow cytometric analysis also indicate that one of the causes of A375-S2 cell death induced by oridonin was apoptosis. The cell death was preceded by the release of cytochrome c from the mitochondria. Twelve hours after treatment with oridonin, the ratio of Bax/Bcl-xL protein expression was increased and release of cytochrome c was decreased by an extracellular signal-regulated kinase (ERK) MAPK inhibitor (PD98059) and a phosphoinositide 3-kinases (PI3-K) inhibitor (wortmannin). A mitochondrial permeability transition (MPT) inhibitor, decylubiquinone, suppressed the release of cytochrome c without affecting Bax expression. The activation of p53 by oridonin was also blocked by wortmannin. In addtion, PD98059 and wortmannin significantly decreased oridonin-induced DNA fragmentation, but the p38 MAPK inhibitor (SB203580) did not after DNA fragmentation. Oridonin induced A375-S2 cell apoptosis by activating parallel p53 and ERK pathways, increasing the ratio of Bax/Bcl-xL protein expression, and promoting the release of cytochrome c into the cytosol, resulting in apoptotic cell death.
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PMID:Cytochrome c release from oridonin-treated apoptotic A375-S2 cells is dependent on p53 and extracellular signal-regulated kinase activation. 1549 67

It has been reported that interleukin-18 (IL-18) is secreted by B16 murine melanoma cells and that this endogenous IL-18 is involved in the immune escape of murine melanoma cells. The present study investigated whether interleukin (IL)-18 can regulate stem cell factor (SCF) expression, known to be associated with melanocyte proliferation, in B16F10 murine melanoma cells. SCF expression was examined by RT-PCR, intracellular FACS analysis, and ELISA in IL-18 antisense transfectants. Transfection with IL-18 antisense cDNA reduced SCF expression and the expression was enhanced by addition of exogenous IL-18. In addition, the effect of IL-18 was blocked by the antioxidant, N-acetyl-L-cysteine (NAC), indicating that IL-18 regulates ROI production, which is involved in SCF production. Furthermore, inhibitors of p38 mitogen-activated protein kinase (MAPK), such as SB203580, blocked enhanced SCF expression, indicating that p38 MAPK activity is required for IL-18-enhanced SCF production. Taken together, these results suggest that IL-18 plays a critical role as a regulatory factor of SCF expression via ROI and p38 MAPK activity in B16F10 murine melanoma cells.
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PMID:IL-18 enhances SCF production of melanoma cells by regulating ROI and p38 MAPK activity. 1558 25

Carnosol, a constant constituent of Rosmarinus officinalis extracts, is a phenolic diterpene shown to have antioxidant and anticarcinogen properties. In our studies, carnosol inhibited the invasion of highly metastatic mouse melanoma B16/F10 cells in vitro. First, the antimetastatic potentials of carnosol were examined by soft agar colony formation assay. Second, carnosol dose-dependently inhibited B16/F10 cell migration and invasion by in vitro transwell assay. Third, the decreasing activity of metalloproteinase was observed by zymographic assay. The result revealed that the treatment of carnosol could diminish the activity of MMP-9 more than MMP-2. Next, we analyzed the amounts of MMP-9 and MMP-2 proteins in the cells. The data indicated MMP-9 protein was also suppressed by carnosol in the same manner. In accordance with the above data, the results of reverse transcriptase polymerase chain reaction (RT-PCR) analysis showed a reduced level of MMP-9 mRNA. Furthermore, carnosol significantly inhibited the tyrosine phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, AKT, p38, JNK and inhibition of activation of transcription factors NFkappa-B and c-Jun. These results lead us to conclude that carnosol could restrict the invasive ability of B16/F10 mouse melanoma cells by reducing MMP-9 expression and activity through suppressing (ERK) 1/2, AKT, p38, and JNK signaling pathway and inhibition of NF-kappaB and AP-1 binding activity. Taken together, these results indicate that carnosol targets MMP-mediated cellular events in cancer cells and provides a new mechanism for its anticancer activity.
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PMID:Carnosol inhibits the invasion of B16/F10 mouse melanoma cells by suppressing metalloproteinase-9 through down-regulating nuclear factor-kappa B and c-Jun. 1562 74

Dracorhodin perchlorate, an anthocyanin red pigment, induces human melanoma A375-S2 cell death through the apoptotic pathway. Caspase-3, -8, -9, and -10 inhibitors partially reversed the cell death induced by dracorhodin perchlorate. Caspase-3 and -8 were activated, followed by the degradation of caspase-3 substrates, the inhibitor of caspase-activated DNase, and poly-(ADP-ribose) polymerase. Dracorhodin perchlorate upregulated the expression ratio of Bax/Bcl-2 and significantly increased the expression of p53 and p21(WAF1) proteins. The cell death was partially reduced by the mitogen-activated protein kinase c-JUN NH2-terminal protein kinase (JNK MAPK) inhibitor (SP600125) and p38 MAPK inhibitor (SB 203580), while the MEK inhibitor (PD98059) augmented cell death; the drug induced sustained phosphorylation of JNK and p38 MAPK. Moreover, the Fas agonistic antibody CH-11 has a synergistic effect with dracorhodin perchlorate. The phoshatidylinositol 3-kinase (PI3-K) family inhibitor wortmanin and tyrosine kinase inhibitor genistein rescued the viability loss induced by dracohodin perchlorate. Taken together, dracorhodin perchlorate induces apoptosis in A375-S2 cells via accumulation of p53, alters the Bax/Bcl-2 ratio, and activates caspases and p38/JNK MAPKs.
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PMID:Dracorhodin perchlorate induces A375-S2 cell apoptosis via accumulation of p53 and activation of caspases. 1568 74

Melanogenesis is one of the characteristic functional activities of melanocyte/melanoma and is regulated via mitogen-activated protein kinase (MAPK) and Akt/protein kinase B (PKB) pathways. Placental total lipid fraction (PTLF), prepared from a hydroalcoholic extract of fresh term human placenta contains sphingolipids and was recently shown to stimulate melanogenesis via up-regulation of the key enzyme tyrosinase in B16F10 mouse melanoma cells. How such lipids mediate their effects on pigmentation and tyrosinase expression is a particularly important aspect of melanogenesis. To study the signaling that leads to tyrosinase expression, we have investigated the roles of the MAPK and Akt/PKB pathways in B16F10 melanoma cells in melanogenesis in response to PTLF. Treatment of cells with PTLF led to the time dependent phosphorylation of p38 MAPK. SB203580, a p38 MAPK inhibitor, completely blocked the PTLF-induced melanogenesis by inhibiting promoter activity and subsequent expression of tyrosinase. Phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002 a blocker of the Akt signaling pathway, or an inhibitor of MEK (MAPK/ERK Kinase), PD98059 when included along with PTLF was found to potentiate PTLF-induced phosphorylation of p38 MAPK together with tyrosinase expression and melanogenesis. The results suggest that the activation of p38 MAPK plays a crucial role in PTLF-induced B16F10 melanogenesis by up-regulating tyrosinase expression.
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PMID:Human placental lipid induces melanogenesis through p38 MAPK in B16F10 mouse melanoma. 1576 Mar 40

Transcription factors of the STAT (signal transducer and activator of transcription) family are important in signal transduction of cytokines. They are subject to post-translational modification by phosphorylation on tyrosine and serine residues. Recent evidence suggested that STATs are methylated on a conserved arginine residue within the N-terminal region. STAT arginine methylation has been described to be important for STAT function and loss of arginine methylation was discussed to be involved in interferon resistance of cancer cells. Here we provide several independent lines of evidence indicating that the issue of arginine methylation of STATs has to be reassessed. First, we show that treatment of melanoma and fibrosarcoma cells with inhibitors used to suppress methylation (N-methyl-2-deoxyadenosine, adenosine, dl-homocysteine) had profound and rapid effects on phosphorylation of STAT1 and STAT3 but also on p38 and Erk signaling cascades which are known to cross-talk with the Jak/STAT pathway. Second, we show that anti-methylarginine antibodies did not precipitate specifically STAT1 or STAT3. Third, we show that mutation of Arg(31) to Lys led to destabilization of STAT1 and STAT3, implicating an important structural role of Arg(31). Finally, purified catalytically active protein arginine methyltransferases (PRMT1, -2, -3, -4, and -6) did not methylate STAT proteins, and cotransfection with PRMT1 did not affect STAT1-controlled reporter gene activity. Taken together, our data suggest the absence of arginine methylation of STAT1 and STAT3.
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PMID:Are STATS arginine-methylated? 1582 48

Reactive oxygen species (ROS) comprise a group of noxious byproducts of oxidative processes which participate in the induction of many common diseases. However, understanding their role in the regulation of normal physiological redox signaling is currently evolving. Detailed study of the dynamic functions of ROS within the biological milieu is difficult because of their high chemical reactivity, short lifetime, minute concentrations and cytotoxicity at high concentrations. In this study, we show that increasing intracellular ROS levels, set off by controlled in situ photogeneration of a nontoxic bacteriochlorophyll-based sensitizer initiate responses in cultured melanoma cells. Using hydroethidine as detector, we determined light-dependent generation of superoxide and hydroxyl radicals in cell-free and cell culture models. Monitoring the ROS-induced responses revealed individual and differential behavior of protein kinases [p38, mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and Akt] as well as effects on the subcellular distribution of phosphorylated p38. Furthermore, alterations in morphology and motility and effects on cell viability as a function of time and photosensitizer doses were observed. Following mild ROS challenge, enzymatic and cellular changes were observed in the majority of the cells, without inducing extensive cell death. However, upon vigorous ROS challenge, a similar profile of the overall responses was observed, terminating in cell death. This study shows that precisely controlled photogeneration of ROS can provide simple, fine-tuned, noninvasive manipulation of ROS-sensitive cellular responses ranging from individual enzymes to gross behavior of target cells. The observations made with this tool enable a dynamic and causal correlation, presenting a new alternative for studying the role of ROS in cellular redox signaling.
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PMID:Manipulation of redox signaling in mammalian cells enabled by controlled photogeneration of reactive oxygen species. 1584 Jun 54

We have reported that caspase cascade accompanied by the regulation of Bax/Bcl-2 and MAPK signaling were involved in evodiamine-induced A375-S2 cell death. In this study, pretreatment with interleukin 1 (IL-1) receptor antagonist (IL-1Ra) rescued the cell viability loss and reversed the ratio of terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL)-positive cells induced by evodiamine. IL-1Ra was capable of attenuating the expression of Fas-ligand (Fas-L) and the cleavage of procaspas-8 and -3 caused by evodiamine. Subsequently, IL-1Ra reduced evodiamine-induced DNA degradation, p53 activation and up-regulation of Bax/Bcl-2 ratio. However, IL-1Ra attenuated the enhanced phosphorylation level of p38 mitogen-activated protein kinase (p38 MAPK) without affecting extracellular signal-regulated protein kinase (ERK) inactivation induced by evodiamine. In conclusion, IL-1-induced death cascade in melanoma A375-S2 cell might be one of the targets for natural product evodiamine, and increased Fas-L expression via IL-1 mediated pathway stands at the initiation phase, leading to consequent events that culminate in the death of the cells.
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PMID:Evodiamine induced human melanoma A375-S2 cell death partially through interleukin 1 mediated pathway. 1593 Jul 31

Transforming growth factor beta (TGF-beta) is a multifunctional cytokine involved in the regulation of cell proliferation, differentiation and survival/or apoptosis of many cells. Knock-out experiments in mice for the three isoforms of TGF-beta have demonstrated their importance in regulating inflammation and tissue repair. TGF-beta is implicated in the pathogenesis of human diseases, including tissue fibrosis and carcinogenesis. TGF-beta receptors act through multiple intracellular pathways. Upon binding of TGF-beta with its receptor, receptor-regulated Smad2/3 proteins become phosphorylated and associate with Smad4. Such complex translocates to the nucleus, binds to DNA and regulates transcription of specific genes. Negative regulation of TGF-beta/Smad signalling may occur through the inhibitory Smad6/7. Furthermore, TGF-beta-activated kinase-1 (TAK1) is a component of TGF-beta signalling and activates stress-activated kinases: p38 through MKK6 or MKK3 and c-Jun N-terminal kinases (JNKs) via MKK4. In the brain TGF-beta, normally expressed at the very low level, increases dramatically after injury. Increased mRNA levels of the three TGF-beta isoforms correlate with the degree of malignancy of human gliomas. TGF-betas are secreted as latent precursors requiring activation into the mature form. TGF-beta may contribute to tumour pathogenesis by direct support of tumour growth and influence on local microenvironment, resulting in immunosuppression, induction of angiogenesis, and modification of the extracellular matrix. TGF-beta1,2 may stimulate production of vascular endothelial growth factor (VEGF) as well as plasminogen activator inhibitor (PAI-I), that are involved in vascular remodelling occurring during angiogenesis. Blocking of TGF-beta action inhibits tumour viability, migration, metastases in mammary cancer, melanoma and prostate cancer model. Reduction of TGF-beta production and activity may be a promising target of therapeutic strategies to control tumour growth.
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PMID:TGF beta signalling and its role in tumour pathogenesis. 1599 Sep 18

6-Nitro-7-hydroxycoumarin (6-NO2-7-OHC) and 3,6,8-trinitro-7-hydroxycoumarin (3,6,8-NO2-7-OHC) have previously been shown to be potent and selective anti-proliferative agents in a human melanoma cell line. These agents functioned by decreasing DNA synthesis, through an inhibition of the S phase regulatory protein, cyclin A. However, the key molecular target(s) for these drugs remained undefined. Here, we attempted to elucidate the exact nature of the relationship between drug exposure and signal transduction, particularly their effects on the mitogen activated protein kinase (MAPK) cascades, and the consequent effect on cell growth, death and differentiation. Comparative studies were carried out using 7-hydroxycoumarin (7-OHC). Both nitro-derivatives were found to alter the phosphorylation status of ERK1/ERK2 and p38. However, 7-OHC exerted this effect only at higher concentrations and longer incubation times. Also, none of the three drugs had any effect on SAPK phosphorylation. Tyrosinase activity assays and morphological studies were used to show drug-induced effects on cellular differentiation. Unlike 7-OHC, both 6-NO2-7-OHC and 3,6,8-NO2-7-OHC caused a dramatic increase in tyrosinase activity in a manner similar to the cAMP elevating agent, forskolin. Also, the MEK inhibitor (PD98059) in combination with nitro-derivatives stimulated an even greater increase in tyrosinase activity when compared to either drug. In addition, the p38 inhibitor (SB203580) reduced the activity of both drugs. Morphological examination of treated cells showed nitro-derivatives caused changes consistent with altered cellular differentiation. Taken together, we have established that exposure of human malignant melanoma cells to these drugs leads to a modulation of p38 MAP kinase phosphorylation. This implies that these drugs may function by altering both melanogenesis and cellular differentiation. However, their effect on the levels of these proteins rather than their phosphorylation status remains to be determined. Therefore, additional studies are underway in order to identify the exact binding partners for these drugs.
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PMID:Activation of mitogen activated protein kinase pathways and melanogenesis by novel nitro-derivatives of 7-hydroxycomarin in human malignant melanoma cells. 1599 58


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