Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Atiprimod is a novel cationic amphiphilic compound and has been shown to exert antimyeloma effects both in vitro and in mouse experiments. This study was undertaken to evaluate the therapeutic efficacy of atiprimod on mantle cell lymphoma (MCL) and elucidate the mechanism by which it induces cell apoptosis. Atiprimod inhibited the growth and induced apoptosis of MCL cell lines and freshly isolated primary tumor cells in vitro. More importantly, atiprimod significantly inhibited tumor growth in vivo and prolonged the survival of tumor-bearing mice. However, atiprimod also exhibited lower cytotoxicity toward normal lymphocytes. Atiprimod activated c-Jun N-terminal protein kinases (JNK) and up-regulated the level of Bax, Bad, and phosphorylated Bcl-2, resulting in release of apoptosis-inducing factor (AIF) and cytochrome c from mitochondria and activation and cleavage of caspase-9, caspase-3, and PARP. However, AIF, but not activation of caspases or PARP, was responsible for apoptosis in MCL cells because an AIF inhibitor, but not pan-caspase or paspase-9 inhibitors, completely abrogated atiprimod-induced apoptosis. Taken together, our results demonstrate that atiprimod displays a strong anti-MCL activity. Cell apoptosis was induced mainly via activation of the AIF pathway. These results support the use of atiprimod as a potential agent in MCL chemotherapy.
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PMID:Atiprimod inhibits the growth of mantle cell lymphoma in vitro and in vivo and induces apoptosis via activating the mitochondrial pathways. 1731 53

Histone deacetylase (HDAC) inhibitors represent a promising group of anticancer agents. This paper shows that the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) stimulated at 5-10 microM apoptosis in human hepatoma HepG2 and Huh6 cells, but was ineffective in primary human hepatocytes (PHH). In HepG2 cells SAHA induced the extrinsic apoptotic pathway, increasing the expression of both FasL and FasL receptor and causing the activation of caspase-8. Moreover, SAHA enhanced the level of Bim proteins, stimulated alternative splicing of the Bcl-X transcript with the expression of the proapoptotic Bcl-Xs isoform, induced degradation of Bid into the apoptotic factor t-Bid and dephosphorylation and inactivation of the anti-apoptotic factor Akt. Consequently, SAHA caused loss of mitochondrial transmembrane potential, release of cytochrome c from mitochondria, activation of caspase-3 and degradation of PARP. Interestingly, a combination of suboptimal doses of SAHA (1 microM) and bortezomib (5-10 nM), a potent inhibitor of 26S proteasome, synergistically induced apoptosis in both HepG2 and Huh6 cells, but was ineffective in PHH. Combined treatment increased with synergistic effects the expression levels of c-Jun, phospho-c-Jun and FasL and the production of Bcl-Xs. These effects were accompanied by activation of Bid, caspase-8 and 3. In conclusion, SAHA stimulated apoptosis in hepatoma cells and exerted a synergistic apoptotic effect when combined with bortezomib. In contrast, these treatments were quite ineffective in inducing apoptosis in PHH. Thus, our results suggest the potential application of the SAHA/bortezomib combination in clinical trials for liver cancer.
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PMID:SAHA induces apoptosis in hepatoma cells and synergistically interacts with the proteasome inhibitor Bortezomib. 1735 39

Sangivamycin has shown a potent antiproliferative activity against a variety of human cancers. However, little is known about the mechanism of action underlying its antitumor activity. Here we demonstrate that sangivamycin has differential antitumor effects in drug-sensitive MCF7/wild type (WT) cells, causing growth arrest, and in multidrug-resistant MCF7/adriamycin-resistant (ADR) human breast carcinoma cells, causing massive apoptotic cell death. Comparisons between the effects of sangivamycin on these two cell lines allowed us to identify the mechanism underlying the apoptotic antitumor effect. Fluorescence-activated cell sorter analysis indicated that sangivamycin induced cell cycle arrest in the G(2)/M phase in MCF7/ADR cells. A marked induction of c-Jun expression as well as phosphorylation of c-Jun and JNK was observed after sangivamycin treatment of MCF7/ADR cells but not MCF7/WT cells. Sangivamycin also induced cleavage of lamin A and poly(ADP-ribose) polymerase (PARP) in MCF7/ADR cells, probably via activation of caspase-6, -7, and -9. Pretreatment with a caspase-9-specific inhibitor or pan-caspase inhibitor abolished sangivamycin-induced cleavage of lamin A and PARP but not sangivamycin induction of c-Jun expression and phosphorylation. Pretreatment of MCF7/ADR cells with SP600125, a specific inhibitor of JNK, or with rottlerin, a specific inhibitor of protein kinase Cdelta (PKCdelta), significantly reduced the sangivamycin-induced apoptosis and almost completely abolished sangivamycin-induced phosphorylation of c-Jun and cleavage of lamin A and PARP. Transfection of MCF7/ADR cells with PKCdelta small interfering RNAs or PKCdelta antibody or rottlerin pretreatment significantly suppressed the phosphorylation of JNK. Taken together, our data suggest that sangivamycin induces mitochondria-mediated apoptotic cell death of MCF7/ADR cells via activation of JNK in a protein kinase Cdelta-dependent manner.
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PMID:The nucleoside analog sangivamycin induces apoptotic cell death in breast carcinoma MCF7/adriamycin-resistant cells via protein kinase Cdelta and JNK activation. 1737 72

Here we investigated the cytotoxicity of JS-K, a prodrug designed to release nitric oxide (NO(*)) following reaction with glutathione S-transferases, in multiple myeloma (MM). JS-K showed significant cytotoxicity in both conventional therapy-sensitive and -resistant MM cell lines, as well as patient-derived MM cells. JS-K induced apoptosis in MM cells, which was associated with PARP, caspase-8, and caspase-9 cleavage; increased Fas/CD95 expression; Mcl-1 cleavage; and Bcl-2 phosphorylation, as well as cytochrome c, apoptosis-inducing factor (AIF), and endonuclease G (EndoG) release. Moreover, JS-K overcame the survival advantages conferred by interleukin-6 (IL-6) and insulin-like growth factor 1 (IGF-1), or by adherence of MM cells to bone marrow stromal cells. Mechanistic studies revealed that JS-K-induced cytotoxicity was mediated via NO(*) in MM cells. Furthermore, JS-K induced DNA double-strand breaks (DSBs) and activated DNA damage responses, as evidenced by neutral comet assay, as well as H2AX, Chk2 and p53 phosphorylation. JS-K also activated c-Jun NH(2)-terminal kinase (JNK) in MM cells; conversely, inhibition of JNK markedly decreased JS-K-induced cytotoxicity. Importantly, bortezomib significantly enhanced JS-K-induced cytotoxicity. Finally, JS-K is well tolerated, inhibits tumor growth, and prolongs survival in a human MM xenograft mouse model. Taken together, these data provide the preclinical rationale for the clinical evaluation of JS-K to improve patient outcome in MM.
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PMID:JS-K, a GST-activated nitric oxide generator, induces DNA double-strand breaks, activates DNA damage response pathways, and induces apoptosis in vitro and in vivo in human multiple myeloma cells. 1738 1

Head and neck squamous cell carcinoma (HNSCC) is characterized by epidermal growth factor receptor (EGFR) overexpression, where EGFR levels correlate with survival. To date, EGFR targeting has shown limited antitumor effects in head and neck cancer when administrated as monotherapy. We previously identified a gastrin-releasing peptide/gastrin-releasing peptide receptor (GRP/GRPR) aurocrine regulatory pathway in HNSCC, where GRP stimulates Src-dependent cleavage of EGFR proligands with subsequent EGFR phosphorylation and mitogen-activated protein kinase (MAPK) activation. To determine whether GRPR targeting can enhance the antitumor efficacy of EGFR inhibition, we investigated the effects of a GRPR antagonist (PD176252) in conjunction with an EGFR tyrosine kinase inhibitor (erlotinib). Combined blockade of GRPR and EGFR pathways significantly inhibited HNSCC, but not immortalized mucosal epithelial cell, proliferation, invasion, and colony formation. In addition, the percentage of apoptotic cells increased upon combined inhibition. The enhanced antitumor efficacy was accompanied by increased expression of cleaved poly(ADP-ribose) polymerase (PARP) and decreased phospho-EGFR, phospho-MAPK, and proliferating cell nuclear antigen (PCNA). Using reverse-phase protein microarray (RPPA), we further detected decreased expression of phospho-c-Jun, phospho-p70S6K, and phospho-p38 with combined targeting. Cumulatively, these results suggest that GRPR targeting can enhance the antitumor effects of EGFR inhibitors in head and neck cancer.
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PMID:Antitumor mechanisms of combined gastrin-releasing peptide receptor and epidermal growth factor receptor targeting in head and neck cancer. 1743 Nov 20

The HER2/neu oncogene is an important diagnostic and prognostic factor and therapeutic target in breast and other cancers. We developed and characterized a breast cancer cell line (Bam1a) that overexpresses the activated HER2/neu and ErbB-3 and has a gene expression profile consistent with the ErbB-2 genetic signature. We evaluated the effects of the epidermal growth factor receptor (EGFR)/HER2 inhibitor, gefitinib, on this breast tumor line in vitro and in vivo. We characterized the effects of gefitinib on EGFR, HER2, and ErbB-3 phosphorylation by Western blot and determined the effects on downstream signaling through growth, survival, and stress pathways and the effect on proliferation, cell cycle, and apoptosis. Gefitinib treatment diminished phosphorylation of the ErbB-3 > EGFR > HER2/neu and signal transducers and activators of transcriptions in a dose-dependent fashion. Downstream mitogenic signaling through mitogen-activated protein (MAP)/extracellular signal regulated kinase kinase, p44/42 MAP kinase (MAPK) and stress signaling through c-Jun-NH(2)-kinase (JNK) 1 and c-Jun was impaired (1 micromol/L, 4-24 h), leading to cytostasis and cell cycle arrest within 24 h by decreased cyclin D1, cyclin B1, and p(Ser795)Rb and increased p27. Proliferation and colony formation were inhibited at 0.5 and 1 micromol/L, respectively, and correlated with altered gene expression profiles. Diminished survival signaling through Akt, induction of bim, loss of connexin43, and decreased production of vascular endothelial growth factor-D preceded caspase-3 and poly(ADP)ribose polymerase (PARP) cleavage and apoptosis (>50% 2 micromol/L, 48 h). Oral administration of gefitinib was able to prevent the outgrowth of Bam1a tumor cells from palpable lesions, shrink established tumors, eliminate HER2 and HER3 phosphorylation, and decrease MAPK and Akt signaling in vivo. A variant of the Bam1a cell line, IR-5, with acquired ability to grow in 5 micromol/L gefitinib was developed and characterized. IR-5 bears a novel point mutation in the HER2/neu that corresponds to a L726I in the ATP-binding pocket and correlates with a log decrease in sensitivity to gefitinib, increased heterodimerization with EGFR and HER3, and impaired down-regulation. Gene expression profiling of IR-5 showed increased expression of EMP-1, NOTCH-1, FLT-1, PDGFB, and several other genes that may contribute to the resistant phenotype and sustain signaling through MAPK and Akt. This model will be useful in understanding the differences between intrinsic drug sensitivity and acquired resistance in the context of therapeutic strategies that target oncogene addicted diseases.
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PMID:Breast cancer expressing the activated HER2/neu is sensitive to gefitinib in vitro and in vivo and acquires resistance through a novel point mutation in the HER2/neu. 1763 94

The mechanism of acacetin-induced apoptosis of human breast cancer MCF-7 cells was investigated. Acacetin caused 50% growth inhibition (IC50) of MCF-7 cells at 26.4% 0.7% M over 24 h in the MTT assay. Apoptosis was characterized by DNA fragmentation and an increase of sub-G1 cells and involved activation of caspase-7 and PARP (poly-ADP-ribose polymerase). Maximum caspase 7 activity was observed with 100 microM acacetin for 24 h. Caspase 8 and 9 activation cascades mediated the activation of caspase 7. Acacetin caused a reduction of Bcl-2 expression leading to an increase of the Bax:Bcl-2 ratio. It also caused a loss of mitochondrial membrane potential that induced release of cytochrome c and apoptosis inducing factor (AIF) into the cytoplasm, enhancing ROS generation and subsequently resulting in apoptosis. Pretreatment of cells with N-acetylcysteine (NAC) reduced ROS generation and cell growth inhibition, and pretreatment with NAC or a caspase 8 inhibitor (Z-IETD-FMK) inhibited the acacetin-induced loss of mitochondrial membrane potential and release of cytochrome c and AIF. Stress-activated protein kinase/c-Jun NH4-terminal kinase 1/2 (SAPK/ JNK1/2) and c-Jun were activated by acacetin but extracellular-regulated kinase 1/2 (Erk1/2) nor p38 mitogen-activated protein kinase (MAPK) were not. Our results show that acacetin-induced apoptosis of MCF-7 cells is mediated by caspase activation cascades, ROS generation, mitochondria-mediated cell death signaling and the SAPK/JNK1/2-c-Jun signaling pathway, activated by acacetin-induced ROS generation.
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PMID:Acacetin-induced apoptosis of human breast cancer MCF-7 cells involves caspase cascade, mitochondria-mediated death signaling and SAPK/JNK1/2-c-Jun activation. 1784 3

There is mounting evidence implicating the accumulation of intracellular reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease. Recently, considerable attention has been focused on identifying naturally occurring antioxidants that are able to reduce excess ROS and RNS, thereby protecting against oxidative stress and neuron death. The present study investigated the possible protective effects of piceatannol (trans-3,4,3',5'-tetrahydroxystilbene), which is present in grapes and other foods, on hydrogen-peroxide- and peroxynitrite-induced oxidative cell death. PC12 rat pheochromocytoma (PC12) cells treated with hydrogen peroxide or SIN-1 (a peroxynitrite-generating compound) exhibited apoptotic death, as determined by nucleus condensation and cleavage of poly(ADP-ribose)polymerase (PARP). Piceatannol treatment attenuated hydrogen-peroxide- and peroxynitrite-induced cytotoxicity, apoptotic features, PARP cleavage and intracellular ROS and RNS accumulation. Treatment of PC12 cells with hydrogen peroxide or SIN-1 led to down-regulation of Bcl-X(L) and activation of caspase-3 and -8, which were also inhibited by piceatannol treatment. Hydrogen peroxide or SIN-1 treatment induced phosphorylation of the c-Jun-N-terminal kinase (JNK), which was inhibited by piceatannol treatment. Moreover, SP600125 (a JNK inhibitor) significantly inhibited hydrogen-peroxide- and peroxynitrite-induced PC12 cell death, revealing inactivation of the JNK pathway as a possible molecular mechanism for the protective effects of piceatannol against hydrogen-peroxide- and peroxynitrite-induced apoptosis of PC12 cells. Collectively, these findings suggest that the protective effect of piceatannol against hydrogen-peroxide- and peroxynitrite-induced apoptosis of PC12 cells is associated with blocking the activation of JNK and the down-regulation of Bcl-XL.
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PMID:Piceatannol attenuates hydrogen-peroxide- and peroxynitrite-induced apoptosis of PC12 cells by blocking down-regulation of Bcl-XL and activation of JNK. 1786 87

The anti-apoptotic effects of heat-shock protein (Hsp70) were assessed in SCG neurones following nerve growth factor (NGF) withdrawal. The results showed that the virally mediated expression of Hsp70 mirrored the effects of the c-Jun-N-terminal kinase (JNK) binding domain (JBD) of JNK interacting protein (an inhibitor of JNK and c-Jun activation) and suppressed the phosphorylation of c-Jun. Preventing c-Jun transcriptional activity subsequently led to reduced cytochrome c release and prevented caspase activation as indicated by a decrease in poly (ADP-ribose) polymerase-1 (PARP) cleavage. Together, these results show that Hsp70 is a highly effective inhibitor of apoptosis in sympathetic neurones and that it mediates this effect primarily by suppressing c-Jun transcriptional signalling.
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PMID:Hsp70 suppresses apoptosis in sympathetic neurones by preventing the activation of c-Jun. 1797 Nov 27

The cellular response to insult occurs by signaling via the stress-activated protein kinases, p38, and c-Jun NH(2)-terminal kinase (JNK). In the present study, we determined if hyperosmotic stress to rat hippocampal slices activates p38 and JNK and whether hyperosmolarity is a potential apoptotic stimulus in this experimental paradigm. Hyperosmotic stress, produced by addition of sorbitol to the incubation buffer, increased p38 phosphorylation; in contrast, JNK phosphorylation was not increased above control levels. Activation of p38 by phosphorylation was detected within 15 min of osmotic stress and was maintained through 360 min of hyperosmolarity. Concurrently, levels of cytochrome c were increased in the cytosolic fraction, indicating a decline in mitochondrial integrity. To a greater extent than the apoptotic stimulus, staurosporine, hyperosmotic stress activated caspase-3. Exposure to sorbitol also resulted in cleavage of the nuclear repair enzyme, poly(ADP-ribose) polymerase (PARP) and induced DNA fragmentation in slices. Concomitant treatment with sorbitol and SB202190, a selective p38 inhibitor, prevented the increase in cytosolic cytochrome c, decreased caspase-3 activation, and partially reduced PARP cleavage in a concentration-dependent manner. Inhibition of JNK with SP600125 did not affect caspase-3 activation in hippocampal slices. These results reveal hyperosmotic stress to be a potent activator of caspase-3 in hippocampus and suggest that downstream correlates of p38 signaling through a mitochondrial apoptotic pathway contribute significantly in the response to this insult.
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PMID:Hyperosmotic stress-induced caspase-3 activation is mediated by p38 MAPK in the hippocampus. 1799 51


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