Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006826 (cancer)
 1,092,456 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A novel anticancer drug, cytotrienin A, isolated from Streptomyces sp., induces apoptosis (or programmed cell death) in human promyelocytic leukemia HL-60 cells within 4 h. To elucidate the mechanism of this process, we performed an in-gel kinase assay using myelin basic protein (MBP) as a substrate and found the activation of kinase with an apparent molecular mass of 36 kDa (p36 MBP kinase). The dose of cytotrienin A required to activate p36 MBP kinase was consistent with that required to induce apoptotic DNA fragmentation in HL-60 cells. This p36 MBP kinase was activated with kinetics distinct from the activation of JNK (c-Jun N-terminal kinase)/stress-activated protein kinase and p38 MAPK (mitogen-activated protein kinase). Importantly, the p36 MBP kinase was immunologically different from MAPK superfamily molecules such as ERK1, JNK isoforms, and p38 MAPK. In addition, the p36 MBP kinase activation and apoptotic DNA fragmentation were inhibited by antioxidants such as N-acetylcysteine and reduced-form glutathione. The p36 MBP kinase activation was also observed during hydrogen peroxide (H2O2) and okadaic acid-induced apoptosis. Although a specific inhibitor of caspase-3-like proteases (Ac-DEVD-CHO) or a specific inhibitor of caspase-1-like proteases (Ac-YVAD-CHO) did not block the cytotrienin A-, H2O2-, or okadaic acid-induced apoptosis, a broad specificity inhibitor of caspases (Z-Asp-CH2-DCB) strongly inhibited the apoptosis of HL-60 cells. Surprisingly, Z-Asp-CH2-DCB inhibited the activation of p36 MBP kinase induced by cytotrienin A or H2O2, but did not inhibit the activation of JNK/stress-activated protein kinase and p38 MAPK. Taken together, these results indicate that p36 MBP kinase activation is downstream of the activation of Z-Asp-CH2-DCB-sensitive caspases, and reactive oxygen species could be included in the apoptotic events. Moreover, according to the Western blotting using the antibodies against MST1/Krs2 or MST2/Krs1, it is suggested that the p36 MBP kinase is an active proteolytic product of MST1/Krs2 and MST2/Krs1, which are originally cloned by virtue of its homology to the budding yeast Ste20 kinase. Thus, the p36 MBP kinase might be a common component of the diverse signaling pathways leading to apoptosis, and controlling this p36 MBP kinase pathway might be a novel strategy for cancer chemotherapy.
Cancer Res 1998 Nov 01
PMID:Caspase-mediated activation of a 36-kDa myelin basic protein kinase during anticancer drug-induced apoptosis. 980 95

EMMPRIN (extracellular matrix metalloproteinase inducer) stimulates fibroblast metalloproteinases (MMP) 1, 2 and 3 (Kataoka et al. (1993) Cancer Res. 53, 3154-3158). Here we focus on MMP-1, showing that in lung tumors, MMP-1's cognate mRNA is strongly expressed in stromal fibroblasts adjacent to EMMPRIN-expressing tumor cells. In vitro, EMMPRIN upregulates MMP-1 mRNA expression in a concentration-dependent manner, with a peak accumulation at 24 h. The response is genistein-sensitive, suggesting it is dependent on tyrosine kinase activity. Analysis of tyrosine phosphorylation-dependent MAP kinases ERK 1/2, SAPK/JNK, and p38 showed that the activity of p38 but not that of the other 2 kinases was elevated in response to EMMPRIN. That p38 activity was required for EMMPRIN stimulation of MMP-1 was evident from results showing that the p38 inhibitor SB203580 blocked this response. This is the first available information regarding the mechanism by which tumor-associated molecules upregulate MMP synthesis in stromal fibroblasts.
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PMID:Tumor-derived EMMPRIN (extracellular matrix metalloproteinase inducer) stimulates collagenase transcription through MAPK p38. 987 71

beta-Hydroxyisovalerylshikonin (beta-HIVS), which was isolated from the plant, Lithospermium radix, inhibited the growth of various lines of cancer cells derived from human solid tumors at low concentrations between 10(-8) and 10(-6) M. When HL-60 cells were treated with 10(-6) M beta-HIVS for 3 h, characteristic features of apoptosis, such as DNA fragmentation, nuclear fragmentation, and activation of caspase-3-like activity, were observed. The most characteristic features of the effect of beta-HIVS were the remarkable morphological changes induced upon treatment of HL-60 cells with beta-HIVS, as visualized on the staining of actin filaments with phalloidin labeled with tetramethylrhodamine B isothiocyanate. Moreover, activation of MAP kinases, such as ERK2, JNK and p38, was detected after treatment with 10(-6) M beta-HIVS preceding the appearance of the characteristics of apoptosis, and the features of the activation of these MAP kinases were quite different from those of Fas and anticancer drug-induced apoptosis. The activation of JNK by beta-HIVS was not inhibited by inhibitors of caspases, suggesting that JNK is located either upstream or independent of the caspase signaling pathway. beta-HIVS did not inhibit the activity of topoisomerase II. These results indicate that beta-HIVS induces apoptosis in HL-60 cells through a mechanism unlike those reported for anti-Fas antibodies and etoposide.
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PMID:beta-hydroxyisovalerylshikonin inhibits the cell growth of various cancer cell lines and induces apoptosis in leukemia HL-60 cells through a mechanism different from those of Fas and etoposide. 988 Jul 90

Epidermal growth factor (EGF) is produced in the ovary and influences proliferation of the malignant ovarian surface epithelium (OSE); yet its role in malignancy or in regulating the normal surface epithelium is unclear. In human OSE cells derived from primary cultures of normal tissue transfected with SV40 large T antigen (IOSE cells), EGF promoted survival but not proliferation. This survival effect was reversed by acute treatment with the phorbol ester, 12-0-tetradecanoyl-13-phorbol acetate (TPA) which alone markedly inhibited IOSE proliferation. We tested whether the activities of the mitogen-activated protein kinases (ERK1/2 and JNK1) varied in response to EGF, TPA, or combinations of these agonists and if the same treatments altered patterns of immediate early gene expression. Alone, EGF activated ERK1/2, increased and sustained levels of c-jun mRNA, but had almost no effect on JNK1 activation. Conversely, PKC activation resulted in a rapid, but transient induction of c-fos RNA and of both kinases, JNK1 and ERK2. When combined, EGF and TPA further enhanced the phosphorylation of both enzymes despite inhibiting survival. Though JNKs and ERKs are thought to transduce opposing cellular responses, in IOSE cells, robust costimulation of the JNK and ERK pathways may redirect the survival message.
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PMID:Regulation of proliferation and apoptosis by epidermal growth factor and protein kinase C in human ovarian surface epithelial cells. 992 63

We report here that stress stimuli such as gamma-irradiation or the anticancer drug doxorubicin activate expression of the death-inducing ligands (DILs) CD95-L, TNF-alpha and TRAIL. Apoptosis induced by gamma-irradiation or doxorubicin engages a FADD- and caspase-dependent apoptosis pathway which is inhibited by dominant negative FADD or the caspase inhibitor zVAD. zVAD did not prevent activity of JNK/SAPKs in response to doxorubicin suggesting that JNK/SAPK activity is independent of death receptor triggering during cellular stress-induced apoptosis. In addition, JNK/SAPKs remained activated by doxorubicin in resistant cell lines in which cleavage of caspases and apoptosis was not observed. These data uncouple JNK/SAPK activation and apoptosis signaling and indicate that cellular stress-induced apoptosis involves signaling via DILs which is paralleled by activation of JNK/SAPKs. Activation of these kinases may contribute e.g., to the expression of molecules involved in apoptosis but is not sufficient for induction of the apoptosis program following cellular stress.
Int J Cancer 1999 Jan 29
PMID:JNK/SAPK activity is not sufficient for anticancer therapy-induced apoptosis involving CD95-L, TRAIL and TNF-alpha. 993 84

We have previously found that epidermal growth factor (EGF) mediates growth through the Jun N-terminal kinase/stress-activated kinase (JNK/SAPK) pathway in A549 human lung carcinoma cells. As observed here, EGF treatment also greatly enhances the tumorigenicity of A549 cells, suggesting an important role for JNK in cancer cell growth (F. Bost, R. McKay, N. Dean, and D. Mercola, J. Biol. Chem. 272:33422-33429, 1997). Several isoforms families of JNK, JNK1, JNK2, and JNK3, have been isolated; they arise from alternative splicing of three different genes and have distinct substrate binding properties. Here we have used specific phosphorothioate oligonucleotides targeted against the two major isoforms, JNK1 and JNK2, to discriminate their roles in EGF-induced transformation. Multiple antisense sequences have been screened, and two high-affinity and specific candidates have been identified. Antisense JNK1 eliminated steady-state mRNA and JNK1 protein expression with a 50% effective concentration (EC50) of <0.1 microM but did not alter JNK2 mRNA or protein levels. Conversely, antisense JNK2 specifically eliminated JNK2 steady-state mRNA and protein expression with an EC50 of 0.1 microM. Antisense JNK1 and antisense JNK2 inhibited by 40 and 70%, respectively, EGF-induced total JNK activity, whereas sense and scrambled-sequence control oligonucleotides had no effect. The elimination of mRNA, protein, and JNK activities lasted 48 and 72 h following a single Lipofectin treatment with antisense JNK1 and JNK2, respectively, indicating sufficient duration for examining the impact of specific elimination on the phenotype. Direct proliferation assays demonstrated that antisense JNK2 inhibited EGF-induced doubling of growth as well as the combination of active antisense oligonucleotides did. EGF treatment also induced colony formation in soft agar. This effect was completely inhibited by antisense JNK2 and combined-antisense treatment but not altered by antisense JNK1 alone. These results show that EGF doubles the proliferation (growth in soft agar as well as tumorigenicity in athymic mice) of A549 lung carcinoma cells and that the JNK2 isoform but not JNK1 is utilized for mediating the effects of EGF. This study represents the first demonstration of a cellular phenotype regulated by a JNK isoform family, JNK2.
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PMID:The Jun kinase 2 isoform is preferentially required for epidermal growth factor-induced transformation of human A549 lung carcinoma cells. 1002 81

EAT/mcl-1 showed increased expression during the differentiation of a multipotent human embryonic carcinoma cell line, NCR-G3, and of myeloblastic cells "ML-1," and has sequence similarity to Bcl-2. In this present study, we determined whether the apoptotic cell death induced by chemotherapeutic agents could be inhibited by EAT/mcl-1, as has been found with Bcl-2. Cells transfected with EAT/mcl-1 showed higher resistance to cis-diammine dichloroplatinum (II) (CDDP) and carboplatin compared with the parental line (10)1 and neomycin-resistance gene-transfected clone, (10)1/neo. There was, however, no difference in sensitivity to etoposide, N,N-bis-(2-chloroethyl)-N'-(3-hydroxypropyl) phosphordiamidic acid cyclic ester monohydrate, adriamycin or other chemotherapeutic agents tested. DNA fragmentation of the parental cells following treatment with CDDP and carboplatin was observed in a concentration-dependent manner. In contrast, cells transfected with EAT/mcl-1 did not show DNA fragmentation following treatment with the same concentration of these drugs. EAT/mcl-1 was capable of delaying the onset of p53-independent apoptosis, although it could not inhibit apoptosis completely. Since CDDP and carboplatin damage DNA and then activate c-abl and the JNK/SAPK pathway, EAT/mcl-1 may inhibit p53-independent apoptosis through a c-abl/JNK (SAPK)-dependent mechanism. EAT/mcl-1 has functional homology to Bcl-2 in that it can enhance cell viability under conditions which otherwise cause apoptosis and increase resistance to chemotherapeutic agents.
Jpn J Cancer Res 1998 Dec
PMID:EAT/mcl-1, a member of the bcl-2 related genes, confers resistance to apoptosis induced by cis-diammine dichloroplatinum (II) via a p53-independent pathway. 1008 94

Mixed lineage kinases (MLKs) form a family of serin/threonine protein kinases with multiple protein/protein interaction domains (SH3, Cdc42 Rac interactive binding sequence, leucine zipper, and proline rich region), the physiological roles of which are largely unknown. We show that overexpression of wild type MLK3 leads to morphological transformation of NIH 3T3 fibroblasts and growth in soft agar. Consistent with this transforming potential, we demonstrate that MLK3 strongly induces transcription from a reporter construct that is driven by a composite AP-1-/Ets-1-enhancer element in HEK 293 cells. In the same cell system, MLK3 preferentially activates the c-Jun NH2-terminal kinase/stress-activated protein kinase (JNK/SAPK) mitogen-activated protein kinase cascade and to a lesser degree the extracellular signal-regulated kinase (ERK) pathway. Activation of the latter can be further enhanced by coexpression of wild type MEK1 and is blocked by the synthetic MEK inhibitor PD 098059 or a kinase-dead MEK1 mutant. Immunoprecipitated MLK3 catalyses the phosphorylation of MEK1 in vitro, but this phosphorylation leads only to a marginal activation. In support of these data, we also show that MEK1 is highly phosphorylated in vivo on Ser 217/221 in MLK3-transformed fibroblasts, whereas activating ERK phosphorylations are barely detectable. Nevertheless, MLK3-transformed NIH 3T3 fibroblasts are partially reverted when activation of MEK is specifically blocked with PD 098059. Our combined data show that although MLK3 is primarily an activator of the JNK/SAPK pathway, overexpression of the wild type protein leads to a transformed phenotype in NIH 3T3 cells that can be partially reversed by a synthetic MEK inhibitor. We conclude that the ERK pathway is necessary for MLK3-mediated transformation.
Cancer Res 1999 May 01
PMID:The JNK/SAPK activator mixed lineage kinase 3 (MLK3) transforms NIH 3T3 cells in a MEK-dependent fashion. 1023 8

Trivalent arsenic (arsenite, As3+) is a human carcinogen, which is associated with cancers of skin, lung, liver, and bladder. However, the mechanism by which arsenite causes cancer is not well understood. In this study, we found that exposure of Cl 41 cells, a well characterized mouse epidermal cell model for tumor promotion, to a low concentration of arsenite (<25 microM) induces cell transformation. Interestingly, arsenite induces Erk phosphorylation and increased Erk activity at doses ranging from 0.8 to 200 microM, while higher doses (more than 50 microM) are required for activation of JNK. Arsenite-induced Erk activation was markedly inhibited by introduction of dominant negative Erk2 into cells, while expression of dominant negative Erk2 did not show inhibition of JNK and MEK1/2. Furthermore, arsenite-induced cell transformation was blocked in cells expressing the dominant negative Erk2. In contrast, overexpression of dominant negative JNK1 was shown to increase cell transformation even though it inhibits arsenite-induced JNK activation. Our results not only show that arsenite induces Erk activation, but also for the first time demonstrates that activation of Erk, but not JNK, by arsenite is required for its effects on cell transformation.
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PMID:Requirement of Erk, but not JNK, for arsenite-induced cell transformation. 1032 51

Alkyl-lysophospholipids (ALPs) represent a new class of antitumor drugs that induce apoptotic cell death in a variety of tumor cell lines. Although their precise mechanism of action is unknown, ALPs primarily act on the cell membrane, where they inhibit signaling through the mitogen-activated protein kinase (MAPK) pathway. Because stimulation of the stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK) pathway is essential for radiation-induced apoptosis in certain cell types, we tested the effect of ALPs in combination with ionizing radiation on MAPK/SAPK signaling and apoptosis induction. Here, we present data showing that three ALPs, 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine, hexadecylphosphocholine, and the novel compound octadecyl-(1,1-dimethyl-piperidinio-4-yl)-phosphate (D-21266) induce time- and dose-dependent apoptosis in the human leukemia cell lines U937 and Jurkat T but not in normal vascular endothelial cells. Moreover, in combination with radiation, ALPs strongly enhance the induction of apoptosis in both leukemic cell lines. All tested ALPs not only prevented MAPK activation, but, like radiation, stimulated the SAPK/JNK cascade within minutes. A dominant-negative mutant of c-Jun inhibited radiation- and ALP-induced apoptosis, indicating a requirement for the SAPK/JNK pathway. Our data support the view that ALPs and ionizing radiation cause an enhanced apoptotic effect by modulating the balance between the mitogenic, antiapoptotic MAPK, and the apoptotic SAPK/JNK pathways. This type of modulation of specific signal transduction pathways in tumor cells may lead to the development of new therapeutic strategies.
Cancer Res 1999 May 15
PMID:Alkyl-lysophospholipids activate the SAPK/JNK pathway and enhance radiation-induced apoptosis. 1034 58


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