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: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Arachidonic acid (AA)-induced apoptotic death of human leukemia U937 cells was characteristic of increase in intracellular Ca(2+) concentration ([Ca(2+)]i), ROS generation, ERK inactivation, p38 MPAK activation, degradation of procaspase-8 and production of truncated Bid (tBid). Moreover, AA treatment upregulated Fas/FasL protein expression and transcription of Fas/FasL mRNA. Downregulation of FADD blocked AA-induced procaspase-8 degradation and rescued viability of AA-treated cells. BAPTA-AM (Ca(2+) chelator) pretreatment abolished AA-induced ROS generation, while N-acetylcysteine (NAC, ROS scavenger) was unable to alter AA-elicited [Ca(2+)]i increase. Pretreatment with BAPTA-AM or NAC abrogated p38 MAPK activation and restored ERK activation. Suppression of p38 MAPK or transfection of constitutively active MEK1 abolished AA-induced Fas and FasL upregulation. AA treatment repressed ERK-mediated c-Fos phosphorylation but evoked p38 MAPK-mediated ATF-2 phosphorylation. Knockdown of c-Fos and ATF-2 by siRNA reflected that c-Fos counteracted the effect of ATF-2 on Fas/FasL upregulation. Taken together, our data indicate that Fas/FasL upregulation in AA-treated U937 cells is elicited by Ca(2+)/ROS-mediated suppression of ERK/c-Fos pathway and activation of p38 MAPK/ATF-2, and suggest that autocrine Fas-mediated apoptotoic mechanism is involved in AA-induced cell death.
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PMID:Arachidonic acid induces Fas and FasL upregulation in human leukemia U937 cells via Ca2+/ROS-mediated suppression of ERK/c-Fos pathway and activation of p38 MAPK/ATF-2 pathway. 1972 Jan 22

Apo-1 (Fas/CD95), a cell surface receptor, triggers apoptosis after binding to its physiological ligand, Apo-1L (FasL/CD95L). This study reports that mahanine, purified from the leaves of Murraya koenigii, has a dose- and time-dependent anti-proliferative activity in acute lymphoid (MOLT-3) and chronic myeloid (K562) leukemic cell lines and in the primary cells of leukemic and myeloid patients, with minimal effect on normal immune cells including CD34(+) cells. Leukemic cells underwent phosphatidylserine externalization and DNA fragmentation, indicating mahanine-induced apoptosis. An increase in reactive oxygen species suggests that the mahanine-induced apoptosis was mediated by oxidative stress. A significant drop in the Bcl2/Bax ratio, the loss of mitochondrial transmembrane potential as well as cytochrome c release from the mitochondria to the cytosol suggested involvement of the mitochondrial pathway of apoptosis. Cytochrome c release was followed by the activation of caspase-9, caspase-3 and caspase-7, and cleavage of PARP in both MOLT-3 and K562 cells. In MOLT-3 cells, formation of the Fas-FasL-FADD-caspase-8 heterotetramer occurred, leading to the cleavage of Bid to its truncated form, which consequently resulted in formation of the mitochondrial transmembrane pore. The incubation of MOLT-3 cells with mahanine in the presence of caspase-8 inhibitor or FasL-neutralizing NOK-2 antibody resulted in the decrease of mahanine-induced cell death. Mahanine was also a potent inhibitor of K562 xenograft growth, which was evident in an athymic nude mice model. In summary, these results provide evidence for involvement of the death receptor-mediated extrinsic pathway of apoptosis in the mahanine-induced anticancer activity in MOLT-3 cells, but not in K562 cells, which are deficient in Fas/FasL.
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PMID:Apoptotic effects of mahanine on human leukemic cells are mediated through crosstalk between Apo-1/Fas signaling and the Bid protein and via mitochondrial pathways. 1975 7

Arachidonic acid (AA)-induced apoptotic death of K562 cells (human chronic myeloid leukemic cells) was characteristic of reactive oxygen species (ROS) generation and mitochondrial depolarization. N-Acetylcysteine pretreatment rescued viability of AA-treated cells and abolished mitochondrial depolarization. In contrast to no significant changes in phospho-JNK and phospho-ERK levels, AA evoked notable activation of p38 MAPK. Unlike that of JNK and p38 MAPK, ERK suppression further reduced the viability of AA-treated cells. Increases in Fas/FasL protein expression, caspase-8 activation, the production of tBid and the loss of mitochondrial membrane potential were noted with K562 cells that were treated with a combination of U0126 and AA. Down-regulation of FADD attenuated U0126-evoked degradation of procaspase-8 and Bid. Abolition of p38 MAPK activation abrogated U0126-elicited Fas/FasL up-regulation in AA-treated cells. U0126 pretreatment suppressed c-Fos phosphorylation but increased p38 MAPK-mediated c-Jun phosphorylation. Knock-down of c-Fos and c-Jun protein expression by siRNA suggested that c-Fos counteracted the effect of c-Jun on Fas/FasL up-regulation. Taken together, our data indicate that AA induces the ROS/mitochondria-dependent death pathway and blocks the ERK pathway which enhances the cytotoxicity of AA through additionally evoking an autocrine Fas-mediated apoptotic mechanism in K562 cells.
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PMID:Suppression of ERK signaling evokes autocrine Fas-mediated death in arachidonic acid-treated human chronic myeloid leukemia K562 cells. 1992 99

Novel phytosphingosine derivatives have been developed based on the inhibition of sphingosine kinase, which has been implicated in cell growth and inhibition of ceramide-mediated apoptosis. This study evaluated the cytotoxic effects and underlying mechanisms of action of novel phytosphingosine derivatives, including N-monomethylphytosphingosine (MMPH) and N,N-dimethylphytosphingosine (DMPH) and the pegylated forms MMPH-PEG and DMPH-PEG, in human leukemia HL60 cells. In viability and proliferation assays using WST-1, all four drugs induced suppression of cell growth and viability in a concentration-dependent manner. Among them, DMPH had the highest antileukemic activity and induced apoptosis via caspase-8, caspase-3, and caspase-9 activation. The apoptotic effect was also associated with Fas/FasL upregulation, Bid cleavage, Bcl-2 downregulation, Bax upregulation, mitochondrial membrane depolarization, and cytochrome c release. DMPH decreased the phosphorylation of ERK and inhibited daunorubicin-induced ERK activation. Furthermore, DMPH displayed synergistic cytotoxicity with daunorubicin in a sequence-dependent manner. Our findings indicate that DMPH has potential as an effective cytotoxic agent for leukemia.
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PMID:Cytotoxic effects of novel phytosphingosine derivatives, including N,N-dimethylphytosphingosine and N-monomethylphytosphingosine, in human leukemia cell line HL60. 2000 Dec 29

The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has been used to treat a variety of cancer cells. However, since some gastric cancer cells are resistant to TRAIL, we explored whether reovirus induces cytolysis in TRAIL-resistant gastric cancer cells. We found that TRAIL-resistant SNU-216 gastric cancer cells were susceptible to apoptosis by reovirus infection. Furthermore, co-treatment with reovirus and TRAIL accelerated apoptosis of SNU-216 cells by down-regulation of Akt activation as assessed by a very low activation of Akt in TRAIL-sensitive SNU-668 gastric cancer cells. Inhibition of Akt signaling with wortmannin or suppression of Akt expression with sh-Akt lentivirus promoted reovirus-mediated apoptosis of SNU-216 gastric cancer cells. Reovirus infection also down-regulates the activation of signaling molecules such as Ras and ERK involved in cell proliferation and survival but not the activation of p38 MAPK involved in cellular stress. In addition, the co-treatment with reovirus and TRAIL resulted in cleavage of caspase-8, caspase-9 and Bid, leading to a decrease in the mitochondrial membrane potential, indicating that reovirus may utilize the mitochondrial intrinsic apoptotic pathway in TRAIL-resistant SNU-216 gastric cancer cells. Accordingly, we first demonstrate that reovirus infection down-regulates Akt activation, leading to apoptosis of TRAIL-resistant gastric cancer cells.
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PMID:Reovirus infection induces apoptosis of TRAIL-resistant gastric cancer cells by down-regulation of Akt activation. 2019 49

Apoptosis has been shown to be induced by many agents, including the clinically useful Sorafenib and K vitamins (VKs). Since few agents have activity against pancreas cancer cell growth, we evaluated the role of naturally occurring K vitamins and Sorafenib both independently and together on the growth in culture of pancreas adenocarcinoma cell lines, including PL-5, PANC-1, and MIA PaCa-2. We found that when a K vitamin was combined with Sorafenib, the dose of Sorafenib required for growth inhibition was substantially reduced. Furthermore, growth could be inhibited at doses of each VK plus Sorafenib in combination that were ineffective when used alone. This effect was seen using vitamins K1, K2, and K5. The combination of VK1 plus Sorafenib-induced apoptosis, as determined by both FACS and TUNEL staining. Phospho-ERK and Bcl-2 levels were decreased, but not levels of other bcl-2 family members. Cleavage of caspases 3 and 8, PARP and Bid were all induced by this combination. Vitamin K1 plus Sorafenib combination also resulted in elevated levels of activated c-Jun N-terminal kinase (JNK) and its substrates c-Jun and FasL. JNK inhibition partly antagonized the induction of apoptosis. Thus, combination VK1 plus Sorafenib strongly induced growth inhibition and apoptosis in pancreas cancer cells, involving both inhibition of the RAF/MEK/ERK pathway as well as activation of the JNK, c-Jun and FasL apoptotic pathway. Since both agents are available for human use, the combination is attractive for evaluation against pancreas cancer growth in vivo.
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PMID:Sorafenib combined vitamin K induces apoptosis in human pancreatic cancer cell lines through RAF/MEK/ERK and c-Jun NH2-terminal kinase pathways. 2030 Nov 94

Cantharidin is an active constituent of mylabris, a traditional Chinese medicine. It is a potent and selective inhibitor of protein phosphatase 2A (PP2A) that plays an important role in control of cell cycle, apoptosis, and cell-fate determination. Owing to its antitumor activity, cantharidin has been frequently used in clinical practice. In the present study, we investigated the therapeutic potential of cantharidin in pancreatic cancer. Cantharidin efficiently inhibited the growth of pancreatic cancer cells, but presented a much lighter toxicity effect against normal pancreatic duct cells. It caused G2/M cell-cycle arrest that was accompanied by the down-regulation of cyclin-dependent kinase 1 (CDK1) and up-regulation of p21 expression. It induced apoptosis and elevated the expressions of pro-apoptotic factors tumor necrosis factor-alpha (TNF-alpha), TNF-related apoptosis inducing receptor 1 (TRAILR1), TRAILR2, Bad, Bak, and Bid, and decreased the expression of anti-apoptotic Bcl-2. Activation of caspase-8 and caspase-9 suggested that both extrinsic and intrinsic pathways are involved in the induction of apoptosis. Interestingly, unlike previous studies on other cancer cells, we found that the inhibitory role of cantharidin is independent of oxidative stress in pancreatic cancer cells. Mitogen-activated protein kinases (MAPKs), including ERK, JNK, and p38, were activated after treatment with cantharidin. Inhibition of JNK, but not ERK or p38, alleviated the cytotoxity effect of cantharidin, suggesting cantharidin exerted its anticancer effect through the JNK-dependent way. Hence, in addition to being an attractive candidate compound with therapeutic potential, cantharidin also highlighted the possibility of using PP2A as a therapeutic target for pancreatic cancer treatment.
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PMID:Cantharidin, a potent and selective PP2A inhibitor, induces an oxidative stress-independent growth inhibition of pancreatic cancer cells through G2/M cell-cycle arrest and apoptosis. 2033 21

To verify whether piceatannol-induced death of leukemia cells was associated with Fas-mediated death pathway, the present study was conducted. Piceatannol-induced apoptotic death of human leukemia U937 cells was characterized by increase in intracellular Ca(2+) concentration ([Ca(2+)]i), ERK inactivation, p38 MPAK activation, degradation of procaspase-8 and production of t-Bid. Piceatannol treatment increased Fas and FasL protein expression, and up-regulated transcription of Fas and FasL mRNA. Down-regulation of FADD blocked piceatannol-induced procaspase-8 degradation and rescued viability of piceatannol-treated cells. Abolition of piceatannol-induced increase in [Ca(2+)]i abrogated p38 MAPK activation and up-regulation of Fas and FasL expression, but restored ERK activation and viability of piceatannol-treated cells. Suppression of p38alpha MAPK or transfection of constitutively active MEK1 abolished piceatannol-induced Fas and FasL up-regulation. Piceatannol treatment repressed ERK-mediated c-Fos phosphorylation but evoked p38alpha MAPK-mediated c-Jun and ATF-2 phosphorylation. Knockdown of c-Fos, c-Jun and ATF-2 by siRNA reflected that c-Fos attenuated the effect of c-Jun and ATF-2 on Fas/FasL up-regulation. Taken together, our data indicate that Fas/FasL up-regulation in piceatannol-treated U937 cells is elicited by Ca(2+)/p38alpha MAPK-mediated activation of c-Jun and ATF-2, and suggest that autocrine Fas-mediated apoptotic mechanism is involved in piceatannol-induced cell death.
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PMID:Piceatannol induces Fas and FasL up-regulation in human leukemia U937 cells via Ca2+/p38alpha MAPK-mediated activation of c-Jun and ATF-2 pathways. 2058 Jun 78

We have previously demonstrated that the total saponins of Astragalus membranaceus (AST) possess potential anti-tumorigenic effects in human colon cancer cells and tumor xenografts. In the present study, the proapoptotic effects of AST were investigated in native and cytokine-induced HT-29 cells to further unveil its mechanism of action. Growth-inhibitory action of AST (60 microg/ml) was demonstrated in native HT-29 cells, which was exaggerated in tumor necrosis factor (TNF) (5 ng/ml)-induced cells. These were accompanied by caspase 3 activation, cleavage of poly(ADP-ribose) polymerase and a subsequent increase in apoptotic cell numbers. Furthermore, activation of procaspase 8 indicates that the extrinsic apoptotic pathway was involved, while cleavage of Bid into t-Bid implicates cross-talk with the intrinsic apoptotic pathway. Alternatively, AST caused S and G2/M phase arrest, while in cytokine-induced cells S phase arrest was predominant. Further adding to our recent suggestion on its correlation with phosphatidylinositol 3-kinase (PI3K)-Akt signaling, we have now revealed that AST caused overexpression of PTEN and down-regulation of mammalian target of rapamycin (mTOR) expression. Nevertheless, these events were preceded by a decrease in nuclear factor-kappaB (NF-kappaB)/DNA binding activity with continuous ERK 1/2 activation. Some of these effects became more intense in cytokine-induced cells. Our findings in this study suggest that AST induces the extrinsic apoptotic cascade and causes cell cycle arrest in HT-29 cells by modulation of both mTOR and ERK signaling pathways, of which inhibition of NF-kappaB is important in the latter mechanism. Most of the above processes are more pronounced in cytokine-induced cells.
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PMID:Astragalus saponins modulate mTOR and ERK signaling to promote apoptosis through the extrinsic pathway in HT-29 colon cancer cells. 2066 49

Cell surface proteases have been demonstrated to play an important role in facilitating cell invasion into the extracellular matrix and may contribute significantly to extracellular matrix degradation by metastatic cancer cells. Abundant expression of these enzymes is associated with poor prognosis. Thus, protease inhibitors that repress cell surface proteases may be applicable to cancer therapy. Because soybean Kunitz-type trypsin inhibitor has been found to induce apoptotic death of human leukemia Jurkat cells, anti-leukemia activity of Bungarus multicinctus protease inhibitor-like protein-1 (PILP-1) is thus examined. PILP-1 induced apoptosis of human leukemia U937 cells, characteristic of loss of mitochondrial membrane potential, degradation of procaspase-8, and production of t-Bid. FADD down-regulation neither restored viability of PILP-1-treated cells nor attenuated production of active caspase-8 and t-Bid in PILP-1-treated cells, suggesting that the death receptor-mediated pathway was not involved in the cytotoxicity of PILP-1. It was found that PILP-1-evoked p38 MAPK activation and ERK inactivation led to PILP-1-induced cell death and down-regulation of ADAM17. Knockdown of ADAM17 by siRNA induced death of U937 cells and inactivation of Lyn and Akt. Immunoprecipitation suggested that ADAM17 and Lyn form complexes. Overexpression of ADAM17, LynY507F (gain of function), and constitutively active Akt suppressed the cytotoxic effects of PILP-1. PILP-1-elicited inactivation of Lyn and Akt was abrogated in cells with overexpressed ADAM17 or LynY507F. Taken together, our data indicate that ADAM17-mediated activation of Lyn/Akt maintains the viability of U937 cells and that suppression of the pathway is responsible for PILP-1-induced apoptosis.
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PMID:Suppression of ADAM17-mediated Lyn/Akt pathways induces apoptosis of human leukemia U937 cells: Bungarus multicinctus protease inhibitor-like protein-1 uncovers the cytotoxic mechanism. 2067 48


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