EC:2.7.11.13 - FACTA Search

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Query: EC:2.7.11.13 (protein kinase C)
49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Addition of phorbol 12,13-dibutyrate (PDB) to H 69, H 345, and H 510 small cell lung cancer (SCLC) cells led to a rapid concentration- and time-dependent increase in p42mapk activity. PD 098059 [2-(2'-amino-3'-methoxyphenyl)-oxanaphthalen-4-one], a selective inhibitor of mitogen activated protein kinase (MAPK) kinase 1, prevented activation of p42mapk by PDB in SCLC cells. PDB also stimulated the activation of p90rsk, a major downstream target of p42mapk. The effect of PDB on both p42mapk and p90rsk activation could be prevented by down-regulation of protein kinase C (PKC) by prolonged pretreatment with 800 nM PDB or treatment of SCLC cells with the PKC inhibitor bisindolylmaleimide (GF 109203X), demonstrating the involvement of phorbol ester-sensitive PKCs in the signaling pathway leading to p42mapk activation. Various neuropeptides, such as bradykinin, vasopressin, bombesin, neurotensin, and galanin, which promote clonal growth in SCLC cells, also induced activation of p42mapk in these cells. In particular, galanin and neurotensin stimulated p42mapk activation in SCLC cells by a pathway that was dependent on the activity of PKC. Furthermore, galanin-stimulated clonal growth of SCLC cells in semisolid medium could be prevented by the PKC inhibitor GF 109203X and by PD 098059. Thus, our results suggest that activation of p42mapk plays an important role in neuropeptide-induced growth of SCLC.
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PMID:Galanin, neurotensin, and phorbol esters rapidly stimulate activation of mitogen-activated protein kinase in small cell lung cancer cells. 897 Nov 88

The overexpression of c-myc frequently accompanies the relapse of small cell lung cancer (SCLC) cells and contributes to the poor prognosis of this tumor. In this study, we confirm that transfected c-myc results in decreased homotypic cell aggregation and increased proliferative capacity of SCLC cells when nutrient conditions are adequate. We also find that c-myc contributes to apoptosis when cells are nutrient depleted, and flow cytometry suggests that this enhanced apoptosis is associated with a failure to halt cell cycling, consistent with the experience in other cell types. We previously found that protein kinase C-beta (PKC-beta) expression in NCI H209 (209) SCLC cells increases markedly with c-myc transfection (L. F. Barr et al., Cancer Res., 51: 5514-5519, 1991), and we hypothesized that PKC-beta may mediate some of the effects of c-myc in these cells. We test this hypothesis by transfection of rat PKC-beta 1 and bovine PKC-beta 2 isoforms into 209 cells before and after transfection with c-myc. PKC-beta 1 transfection has no effect on these cells. However, PKC-beta 2 expression has distinct phenotypic consequences. In the parental cells, PKC-beta 2 expression results in increased homotypic cell aggregation and a prolonged doubling time. Furthermore, PKC-beta 2 expression increases the fraction of these cells in G0-G1. In the cells which express a transfected c-myc gene, PKC-beta 2 expression improves the survival of cells in low serum by decreasing myc-induced apoptosis. This effect was associated with, and may be mediated by, a selection for cells in the G0-G1 fraction. We postulate that transfection of c-myc into SCLC cells may select for those expressing the PKC-beta 2 gene because this signal transduction event protects against myc-induced apoptosis.
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PMID:Protein kinase C-beta 2 inhibits cycling and decreases c-myc-induced apoptosis in small cell lung cancer cells. 910 Oct 84

Recent studies suggest that in some tissues GRP receptor activation can both stimulate phospholipase C and the adenylate cyclase pathway and that activation of the latter pathway may be important in mediating some of its well-described growth effects. However, other studies suggest GRP-R may not be coupled to adenylate cyclase. To investigate this possibility, in the present study we determined the coupling of the GRP receptors to each pathway in mouse, rat, and guinea pig pancreatic acini and compared it to that in mouse Swiss 3T3 cells and human SCLC cells, all of which possess well-characterized GRP receptors. Moreover, we tested the effect of PKC activation on the ability of GRP-related peptides to increase cAMP accumulation in these tissues. Changes in cAMP levels were determined with or without IBMX present, with or without forskolin, or both to amplify small increases in cAMP. In mouse, rat and guinea pig pancreatic acini, murine Swiss 3T3 cells and human SCLC cells, GRP-related peptides caused a 600%, 500%, 250%, 300% and 60% increase, respectively, in [3H]IP with 1-3 nM causing a half-maximal effect. In murine Swiss 3T3 cells, IBMX, forskolin, and IBMX plus forskolin caused a 300%, 3500% and 10500% increase in cAMP, respectively. GRP-related peptides and VIP caused an additional 70% increase in cAMP with GRP causing a half-maximal (EC50) increase in cAMP at 2.1 +/- 0.5 nM, which was not significantly different from the EC50 of 3.1 +/- 0.9 nM for increasing [3H]IP in these cells. GRP-related peptides did not stimulate increases in cAMP in mouse, rat or guinea pig pancreatic acini or in SCLC cells either alone, with IBMX or forskolin or both. However, in pancreatic acini IBMX, forskolin or both increased cAMP 3 to 8-, 10 to 500-, and 100 to 1000-fold increase and the addition of VIP caused an additional 20-, 2-, and 3-fold increase in cAMP in the different species. In mouse pancreatic acini with TPA alone or IBMX plus TPA, neither bombesin nor GRP increased cAMP. Furthermore, in mouse pancreatic acini, neither TPA nor TPA plus IBMX altered basal or VIP-stimulated increases in cAMP. In mouse Swiss 3T3 cells TPA significantly increased cAMP stimulated by Bn, GRP or VIP. These results demonstrated that GRP receptor activation in normal tissues from three different species and a human tumoral cell line do not result in adenylate cyclase activation, whereas in Swiss 3T3 cells it causes such activation. The results suggest that the difference in coupling to adenylate cyclase is likely at least partially due to a difference in coupling to an adenylate cyclase subtype whose activation is regulated by PKC. Therefore, the possible growth effects mediated by this receptor in different embryonic or tumoral cells through activation of adenylate cyclase are not likely to be an important intracellular pathway for these effects in normal tissues.
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PMID:The gastrin-releasing peptide receptor is differentially coupled to adenylate cyclase and phospholipase C in different tissues. 919 77

Cholera toxin (ChT) inhibits signals generated by multiple growth factors in human lung cancer cells, resulting in cell growth inhibition. We now report that ChT triggers apoptosis as shown by DNA fragmentation and activation of caspases cleaving poly(ADP-ribose) polymerase and lamin B. Apoptosis induced by ChT in a small cell lung cancer cell line is not affected by manipulations of intracellular cAMP through preincubation with isobutylmethylxanthine but can be modestly increased through inhibition of protein kinase C with chelerythrine. Thus, apoptosis is actively suppressed in lung cancer cells by a ChT-sensitive-growth regulatory pathway, and these observations may have significant implications in the development of novel strategies for lung cancer treatment.
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PMID:Cholera toxin triggers apoptosis in human lung cancer cell lines. 920 66

Transformed growth of human small cell lung cancer (SCLC) is mediated by autocrine signaling through multiple G protein-coupled neuropeptide receptors. To define the role of Gq and its effector, phospholipase Cbeta (PLCbeta), in SCLC growth, we expressed a COOH-terminal fragment of PLCbeta1 (PLCbetaCT) that is catalytically inactive and is predicted to behave as a competitive inhibitor of Gq signaling. Using endogenous muscarinic receptors as indicators of Gq-coupled receptor signaling status, we observed that stable expression of PLCbetaCT in NCI-H345 SCLC cells significantly inhibited muscarinic receptor-mediated phospholipase C activation and intracellular Ca2+ mobilization. In addition, PLCbetaCT expression reduced the basal activity of protein kinase C as well as the receptor-stimulated activity of the extracellular signal-regulated kinases, consistent with the sequential requirement for Gq, PLCbeta, and protein kinase C in the regulation of the extracellular signal-regulated kinases by neuropeptide and muscarinic receptors in SCLC. By contrast, muscarinic agonist stimulation of the c-Jun NH2-terminal kinases was not inhibited in SCLC cells expressing PLCbetaCT, indicating that other G proteins such as the G12,13 family members mediate c-Jun NH2-terminal kinase activation by neuropeptides and muscarinic agonists. Finally, soft agar colony formation by the SCLC cells expressing PLCbetaCT, but not growth in suspension culture, was markedly reduced, indicating that signaling through Gq and PLCbeta by autocrine-signaling neuropeptide receptors is a dominant pathway involved in the transformed growth of SCLC.
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PMID:Expression of catalytically inactive phospholipase Cbeta disrupts phospholipase Cbeta and mitogen-activated protein kinase signaling and inhibits small cell lung cancer growth. 950 Apr 49

Neuropeptides like galanin produced and released by small cell lung cancer (SCLC) cells are considered principal mitogens in these tumors. We identified the galanin receptor type 2 (GALR2) as the only galanin receptor expressed in H69 and H510 cells. Photoaffinity labeling of G proteins in H69 cell membranes revealed that GALR2 activates G proteins of three subfamilies: G(q), G(i), and G(12). In H69 cells, galanin-induced Ca2+ mobilization was pertussis toxin-insensitive. While phorbol ester-induced extracellular signal-regulated kinase (ERK) activation required protein kinase C (PKC) activity, preincubation of H69 cells with the PKC-inhibitor GF109203X had no effect on galanin-dependent ERK activity. A rise of the intracellular calcium concentration was necessary and sufficient to mediate galanin-induced ERK activation. In support of G(i) coupling, stimulation of GALR2 expressed in HEK293 cells inhibited isoproterenol-induced cAMP accumulation and raised cAMP levels in COS-7 cells when coexpressed with a chimeric G alpha(S)-G alpha(i) protein In H69 cells, galanin activated the monomeric GTPase RhoA and induced stress fiber formation in Swiss 3T3 cells expressing GALR2. Thus, we provide the first direct evidence that in SCLC the mitogenic neuropeptide galanin, interacting with GALR2, simultaneously activates multiple classes of G proteins and signals through the G(q) phospholipase C/calcium sequence and a G(12)/Rho pathway. Oncogene (2000) 19, 4199 - 4209
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PMID:The galanin receptor type 2 initiates multiple signaling pathways in small cell lung cancer cells by coupling to G(q), G(i) and G(12) proteins. 1098 May 93

Autocrine and paracrine signaling leading to stimulation of tumor cell growth is a common theme in human cancers. In addition to polypeptide growth factors such as EGF family members which signal through receptor tyrosine kinases, accumulating evidence supports the autocrine and paracrine involvement of specific neuropeptides with defined physiologic actions as neurotransmitters and gut hormones in lung, gastric, colorectal, pancreatic and prostatic cancers. These neuropeptides, including gastrin-releasing peptide, neuromedin B, neurotensin, gastrin, cholecystokinin and arginine vasopressin bind seven transmembrane-spanning receptors that couple to heterotrimeric G proteins. Studies with human small cell lung cancer (SCLC) cells support a requirement for balanced signaling through G(q) and G(12/13) proteins leading to intracellular Ca2+ mobilization, PKC activation and regulation of the ERK and JNK MAP kinase pathways. While specific neuropeptide antagonists offer promise for interrupting the single neuropeptide autocrine systems operating in pancreatic and prostatic cancers, SCLC is exemplified by multiple, redundant neuropeptide autocrine systems such that tumor growth cannot be inhibited with a single specific antagonist. However, a novel class of neuropeptide derivatives based on the substance P sequence have been defined that exhibit broad specificity for neuropeptide receptors and induce apoptosis in SCLC by functioning as biased agonists that stimulate discordant signal transduction. Thus, interruption of autocrine and paracrine neuropeptide signaling with specific antagonists or broad-spectrum biased agonists offer promising new therapeutic approaches to the treatment of human cancers.
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PMID:Autocrine and paracrine signaling through neuropeptide receptors in human cancer. 1131 3

The serine/threonine protein kinase C (PKC) has been implicated in the regulation of drug resistance and cell survival in many types of cancer cells. However, the one or more precise mechanisms remain elusive. In this study, we have identified and determined the mechanism by which PKC-epsilon, a novel PKC isoform, modulates drug resistance in lung cancer cells. Western blot analysis demonstrates that expression of PKC-epsilon, but not other PKC isoforms, is associated with the chemo-resistant phenotype of non-small cell lung cancer (NSCLC) cell lines. Northern blotting and nuclear run-on transcription analysis further reveals that the failure of expression of PKC-epsilon in the chemo-sensitive phenotype of small cell lung cancer (SCLC) cells results from transcriptional inactivation of the gene. Importantly, forced expression of PKC-epsilon in NCI-H82 human SCLC cells confers a significant resistance to the chemotherapeutic drugs, etoposide and doxorubicin. Resistance is characterized by a significant reduction in apoptosis in PKC-epsilon-expressing cells. Treatment of NCI-H82 cells with etoposide induces a series of time-dependent events, including the release of cytochrome c from the mitochondria to the cytosol, activation of caspase-9 and caspase-3, and cleavage of poly(ADP-ribose) polymerase (PARP). All of these events are blocked by PKC-epsilon expression. Furthermore, caspase-specific inhibitors, z-VAD-fmk and z-DEVD-fmk, significantly attenuate the accumulation of sub-G(1) population and block the PARP cleavage in response to etoposide. These results suggest that PKC-epsilon prevents cells from undergoing apoptosis through inhibition of the mitochondrial-dependent caspase activation, thereby leading to cell survival. Finally, down-regulation of PKC-epsilon expression by the antisense cDNA in NSCLC cells results in increased sensitivity to etoposide. Taken together, our findings suggest an important role for PKC-epsilon in regulating survival of lung cancer cells.
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PMID:Protein kinase C-epsilon promotes survival of lung cancer cells by suppressing apoptosis through dysregulation of the mitochondrial caspase pathway. 1212 73

Nordihydroguaiaretic acid (NDGA) 1 is a constituent of the creosote bush Larrea divaricata and is well known to be a selective inhibitor of lipoxygenases. NDGA can also inhibit the platelet derived growth factor receptor and the protein kinase C intracellular signalling family, which both play an important role in proliferation and survival of cancers. Moreover, NDGA induces apoptosis in tumour xenografts. Although it is likely to have several targets of action, NDGA is well tolerated in animals. These encouraging results have prompted interest in the compound for clinical study. However, high concentrations of NDGA are required for efficacy and more potent analogues are required. We have synthesized five analogues of NDGA with different lengths of carbon bridge between the two catechol moieties in order to establish the spacing required for optimum anticancer effect and to compare their activities with NDGA. In order to ascertain if the catechol moieties are essential for anticancer activity, we prepared five analogues of NDGA containing only one hydroxyl group on each aromatic ring. NDGA 1, its racemic form 2, the catechol derivatives 5, 6 with five or six carbon atom bridges and the phenol analogues 8-11 with bridges of three to six carbon atoms all showed similar activity, with IC50 values of approximately 3-5 microM against the H-69 small cell lung cancer cell line. Analogues with shorter (3) or longer bridges (7, 12) were much less active. The most potent analogue was the biscatechol with a four-carbon bridge 4 which was > 10 times more active than NDGA and therefore represents a new lead compound in this area. Surprisingly, the tetramethyl ether 14 of this compound was slightly more active than NDGA, but the trihydroxy analogue 13 was less active than NDGA. The conformationally restricted analogue 15 was also less active than NDGA. In summary, simplification of the structure of NDGA by removal of the methyl groups has produced a new lead compound 4, which is >10 times more potent than NDGA as a proliferative inhibitor of H-69 small cell lung cancer cells.
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PMID:Synthesis and anticancer activity of nordihydroguaiaretic acid (NDGA) and analogues. 1237 79

Nicotine is not only a major component in tobacco but is also a survival agonist that inhibits apoptosis induced by diverse stimuli including chemotherapeutic drugs. However, the intracellular mechanism(s) involved in nicotine suppression of apoptosis is unclear. Bcl2 is a potent antiapoptotic protein and tumor promotor that is expressed in both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) cells. It is possible that nicotine may regulate Bcl2 to stimulate cell survival. Here we report that nicotine can induce Bcl2 phosphorylation exclusively at the serine 70 site in association with prolonged survival of SCLC H82 cells expressing wild-type but not the phosphorylation-deficient S70A mutant Bcl2 after treatment with chemotherapeutic agents (i.e. cisplatin or VP-16). Nicotine induces activation of PKC alpha and the MAPKs ERK1 and ERK2, which are physiological Bcl2 kinases. Furthermore, ET-18-OCH3, a specific phospholipase C (PLC) inhibitor, blocks nicotine-stimulated Bcl2 phosphorylation and promotes apoptosis, suggesting that PLC may be involved in nicotine activation of Bcl2 kinases. Using a genetic approach, the gain-of-function S70E mutant, which mimics Ser(70) site phosphorylation in the flexible loop domain, potently enhances chemoresistance in SCLC cells. Thus, nicotine-induced cell survival results, at least in part, from a mechanism that involves Bcl2 phosphorylation. Therefore, novel therapeutic strategies for lung cancer in which Bcl2 is expressed may be used to abrogate the anti-apoptotic activity of Bcl2 by inhibiting multiple upstream nicotine-activated pathways.
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PMID:A functional role for nicotine in Bcl2 phosphorylation and suppression of apoptosis. 1242 19

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