Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Panobinostat (LBH589) is a highly potent deacetylase inhibitor that has demonstrated clinical efficacy in patients with advanced cutaneous T-cell lymphoma (CTCL). To gain a better understanding of the compound activity in this tumor type, we investigated the cellular and molecular effects of panobinostat using both in vitro and in vivo models of CTCL. All 4 tested CTCL cell lines exhibited very high sensitivity to panobinostat-induced growth inhibition. However, only 2 of 4 lines exhibited significant response to the cytotoxic activity of panobinostat. In a CTCL xenograft mouse tumor model, panobinostat treatment resulted in complete tumor regression. The difference in cell sensitivity to panobinostat-induced death enabled us to further investigate potential mechanisms responsible for tumor sensitivity or resistance. In CTCL cell lines that were insensitive to panobinostat-induced apoptosis, constitutively activated NF-kappaB and high levels of Bcl-2 were observed. Inhibition of Bcl-2 sensitized cells to the cytotoxic activity of panobinostat. Conversely, knockdown of Bax diminished the CTCL cell sensitivity. Interestingly, panobinostat could induce cytotoxicity in vorinostat-resistant CTCL cells by downregulating phosphorylated STAT3 and STAT5 proteins. These studies suggest distinct mechanisms responsible for resistance to different deacetylase inhibitors. We show that the intrinsic apoptotic signaling plays an essential role in mediating panobinostat anticancer activity. Moreover, cancer cell sensitivity to panobinostat treatment may be further improved by combination with inhibition of anti-apoptotic factors. These data provide preclinical support that panobinostat, as a single agent or in combination with other anticancer agents, is a promising therapy for CTCL.
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PMID:Activity of deacetylase inhibitor panobinostat (LBH589) in cutaneous T-cell lymphoma models: Defining molecular mechanisms of resistance. 2012 62

Cardiotoxin III (CTX III), a basic polypeptide with 60 amino acid residues isolated from Naja naja atra venom, has been reported to have anticancer activity. Exposure of MDA-MB-231 cells with 0.03, 0.09, and 0.15 microM of CTX III for 18 h, CTX III-induced cell apoptosis, as evidenced by accumulation of sub-G1 population, externalization of phosphatidylserine, loss of mitochondrial membrane potential (DeltaPsim) with subsequent release of cytochrome c, and activation of both capases-9 and caspase-3. This correlated with up-regulation in Bax and Bad, and down-regulation of various anti-apoptotic proteins, including Bcl-2, Bcl-X(L), and survivin in CTX III-treated cells. Mechanistic studies showed that CTX III suppressed the phosphorylation of JAK2, STAT3, Akt, and activation of PI3K. Moreover, the PI3K inhibitor wortmannin blocked activation of STAT3 and Akt without affecting the JAK2 activation, whereas JAK2 inhibitor AG490 suppressed the levels of phospho-STAT3, phospho-Akt, and PI3K, suggesting that PI3K activation occurs after JAK2 phosphorylation, and both PI3K and JAK2 kinases cooperate to mediate STAT3 and Akt phosphorylation. Both AG490 and wortmannin also led to up-regulation in Bax and Bad, and down-regulation of Bcl-2, Bcl-X(L), and survivin in MDA-MB-231 cells. Taken together, these results indicate that CTX III induces apoptosis in MDA-MB-231 cells via concomitant inactivation of the JAK2, STAT3, PI3K, and Akt signaling pathways.
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PMID:Down-regulation of the JAK2/PI3K-mediated signaling activation is involved in Taiwan cobra cardiotoxin III-induced apoptosis of human breast MDA-MB-231 cancer cells. 2014 42

Prostate carcinoma is the most frequently diagnosed malignancy and the second leading cause of death of men in the United States. To date, no effective therapeutic treatment allows abrogation of the progression of prostate cancer to more invasive forms. In this study, we identified Saussurea involucrata Kar. et Kir., a rare traditional Chinese medicinal herb, as a potential agent for androgen-independent prostate cancer patients and investigated its biological mechanism as an antineoplastic agent. S. involucrata caused a concentration- and time-dependent inhibition of cell proliferation in human hormone-resistant prostate cancer PC-3 cells. Moreover, in vitro studies in a panel of several types of human cancer cell lines revealed that S. involucrata inhibited cell proliferation with high potency. To evaluate the bioactive compounds, we successively extracted the S. involucrata with fractions of methanol (SI-1), ethyl acetate (SI-2), n-butanol (SI-3), and water (SI-4). Among these extracts, SI-2 contains the most effective bioactivity. SI-2 treatment resulted in significant time-dependent growth inhibition together with G1 phase cell cycle arrest and apoptosis in PC3 cells. In addition, SI-2 treatment strongly induced p21WAF1/CIP and p27KIP1 expression, independent of the p53 pathway, and downregulated expression of cyclin D1 and cyclin-dependent kinase 4 (CDK4). SI-2 treatment increased levels of Bax, cytochrome c, activated caspase-3, and active caspase-9 and decreased Bcl-2 expression level. One of the major targets for the therapy in prostate cancer can be epidermal growth factor receptor (EGFR). SI-2 markedly reduced phosphorylation of EGFR and inhibited activation of AKT and STAT3. Moreover, p.o. administration of SI-2 induced a dose-dependent inhibition of PC-3 tumor growth in vivo. In summary, our study identifies S. involucrata as an effective inhibitor of EGFR signaling in human hormone-resistant prostate cancer PC-3 cells. We suggest that S. involucrata could be developed as an agent for the management of EGFR-positive human cancers.
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PMID:Inhibition of epidermal growth factor receptor signaling by Saussurea involucrata, a rare traditional Chinese medicinal herb, in human hormone-resistant prostate cancer PC-3 cells. 2016 59

DNA methyltransferase inhibitors (MTIs) have recently emerged as promising chemotherapeutic or preventive agents for cancer, despite their poorly characterized mechanisms of action. The present study shows that DNA methylation is integral to the regulation of SH2-containing protein tyrosine phosphatase 1 (SHP1) expression, but not for regulation of suppressors of cytokine signalling (SOCS)1 or SOCS3 in colorectal cancer (CRC) cells. SHP1 expression correlates with down-regulation of Janus kinase/signal transducers and activators of transcription (JAK2/STAT3/STAT5) signalling, which is mediated in part by tyrosine dephosphorylation events and modulation of the proteasome pathway. Up-regulation of SHP1 expression was achieved using a DNA MTI, 5-aza-2'-deoxycytidine (5-aza-dc), which also generated significant down-regulation of JAK2/STAT3/STAT5 signalling. We demonstrate that 5-aza-dc suppresses growth of CRC cells, and induces G2 cell cycle arrest and apoptosis through regulation of downstream targets of JAK2/STAT3/STAT5 signalling including Bcl-2, p16(ink4a), p21(waf1/cip1) and p27(kip1). Although 5-aza-dc did not significantly inhibit cell invasion, 5-aza-dc did down-regulate expression of focal adhesion kinase and vascular endothelial growth factor in CRC cells. Our results demonstrate that 5-aza-dc can induce SHP1 expression and inhibit JAK2/STAT3/STAT5 signalling. This study represents the first evidence towards establishing a mechanistic link between inhibition of JAK2/STAT3/STAT5 signalling and the anticancer action of 5-aza-dc in CRC cells that may lead to the use of MTIs as a therapeutic intervention for human colorectal cancer.
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PMID:Inhibition of DNA methyltransferase induces G2 cell cycle arrest and apoptosis in human colorectal cancer cells via inhibition of JAK2/STAT3/STAT5 signalling. 2019 86

Naphtho[1,2-b]furan-4,5-dione (NFD), prepared from 2-hydroxy-1,4-naphthoquinone and chloroacetaldehyde in an efficient one-pot reaction, exhibits an anti-carcinogenic effect. NFD-induced apoptosis in MDA-MB-231 cells, as indicated by the accumulation of sub-G1 population, externalization of phosphatidylserine, loss of mitochondrial membrane potential (DeltaPsim) with subsequent release of cytochrome c, and activation of both capase-9 and caspase-3. This correlated with up-regulation in Bax and Bad, and down-regulation of various anti-apoptotic proteins, including Bcl-2, Bcl-X(L), Mcl-1, and survivin in NFD-treated cells. In the analysis of signal transduction pathway, NFD suppressed the phosphorylation of JAK2 in MDA-MB-231 cells without altering the expression of JAK2 protein. Activation of STAT3, Src, and PI3K/Akt were also inhibited by NFD. Moreover, the JAK2 inhibitor AG490 blocked JAK2, STAT3, Src, PI3K, and Akt activation, whereas both Src inhibitor PP2 and PI3K inhibitor wortmannin did not affect JAK2 activation. This suggests that STAT3, Src, and PI3K/Akt are downstream molecules of the JAK2 signaling pathway. AG490 treatment also mimics the cytotoxic effects of NFD. Taken together, these results indicate that NFD disrupts JAK2 pathway and induces apoptosis in MDA-MB-231 cells.
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PMID:Naphtho[1,2-b]furan-4,5-dione disrupts Janus kinase-2 and induces apoptosis in breast cancer MDA-MB-231 cells. 2019 88

DAB2IP (DOC-2/DAB2 interactive protein) is a member of the RAS-GTPase-activating protein family. It is often downregulated in metastatic prostate cancer and has been reported as a possible prognostic marker to predict the risk of aggressive prostate cancer. In this study, we furnish several lines of evidence indicating that metastatic human prostate cancer PC3 cells deficient in DAB2IP (shDAB2IP) exhibit increased clonogenic survival in response to ionizing radiation (IR) compared with control cells expressing an endogenous level of DAB2IP (shVector). Radioresistance was also observed in normal prostate cells that are deficient in DAB2IP. This enhanced resistance to IR in DAB2IP-deficient prostate cancer cells is primarily due to faster DNA double-strand break (DSB) repair kinetics. More than 90% of DSBs were repaired in shDAB2IP cells by 8 hours after 2 Gy radiation, whereas only 60% of DSB repair were completed in shVector cells at the same time. Second, upon irradiation, DAB2IP-deficient cells enforced a robust G(2)-M cell cycle checkpoint compared with control cells. Finally, shDAB2IP cells showed resistance to IR-induced apoptosis that could result from a striking decrease in the expression levels of proapoptotic proteins caspase-3, caspase-8, and caspase-9, and significantly higher levels of antiapoptotic proteins Bcl-2 and STAT3 than those in shVector cells. In summary, DAB2IP plays a significant role in prostate cell survival following IR exposure due to enhanced DSB repair, robust G(2)-M checkpoint control, and resistance to IR-induced apoptosis. Therefore, it is important to identify patients with dysregulated DAB2IP for (a) assessing prostate cancer risk and (b) alternative treatment regimens.
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PMID:Downregulation of human DAB2IP gene expression in prostate cancer cells results in resistance to ionizing radiation. 2033 35

Enteropathy-associated T cell lymphoma is a severe complication of celiac disease (CD). One mechanism suggested to underlie its development is chronic exposure of intraepithelial lymphocytes (IELs) to potent antiapoptotic signals initiated by IL-15, a cytokine overexpressed in the enterocytes of individuals with CD. However, the signaling pathway by which IL-15 transmits these antiapoptotic signals has not been firmly established. Here we show that the survival signals delivered by IL-15 to freshly isolated human IELs and to human IEL cell lines derived from CD patients with type II refractory CD (RCDII) - a clinicopathological entity considered an intermediary step between CD and enteropathy-associated T cell lymphoma - depend on the antiapoptotic factors Bcl-2 and/or Bcl-xL. The signals also required IL-15Rbeta, Jak3, and STAT5, but were independent of PI3K, ERK, and STAT3. Consistent with these data, IELs from patients with active CD and RCDII contained increased amounts of Bcl-xL, phospho-Jak3, and phospho-STAT5. Furthermore, incubation of patient duodenal biopsies with a fully humanized human IL-15-specific Ab effectively blocked Jak3 and STAT5 phosphorylation. In addition, treatment with this Ab induced IEL apoptosis and wiped out the massive IEL accumulation in mice overexpressing human IL-15 in their gut epithelium. Together, our results delineate the IL-15-driven survival pathway in human IELs and demonstrate that IL-15 and its downstream effectors are meaningful therapeutic targets in RCDII.
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PMID:IL-15 triggers an antiapoptotic pathway in human intraepithelial lymphocytes that is a potential new target in celiac disease-associated inflammation and lymphomagenesis. 2044 74

The purpose of this study was to evaluate the anticancer potency and mechanism of a novel difluorodiarylidenyl piperidone (H-4073) and its N-hydroxypyrroline modification (HO-3867) in human ovarian cancer. Studies were done using established human ovarian cancer cell lines (A2870, A2780cDDP, OV-4, SKOV3, PA-1, and OVCAR3) as well as in a murine xenograft tumor (A2780) model. Both compounds were comparably and significantly cytotoxic to A2780 cells. However, HO-3867 showed a preferential toxicity toward ovarian cancer cells while sparing healthy cells. HO-3867 induced G(2)-M cell cycle arrest in A2780 cells by modulating cell cycle regulatory molecules p53, p21, p27, cyclin-dependent kinase 2, and cyclin, and promoted apoptosis by caspase-8 and caspase-3 activation. It also caused an increase in the expression of functional Fas/CD95 and decreases in signal transducers and activators of transcription 3 (STAT3; Tyr705) and JAK1 phosphorylation. There was a significant reduction in STAT3 downstream target protein levels including Bcl-xL, Bcl-2, survivin, and vascular endothelial growth factor, suggesting that HO-3867 exposure disrupted the JAK/STAT3 signaling pathway. In addition, HO-3867 significantly inhibited the growth of the ovarian xenografted tumors in a dosage-dependent manner without any apparent toxicity. Western blot analysis of the xenograft tumor tissues showed that HO-3867 inhibited pSTAT3 (Tyr705 and Ser727) and JAK1 and increased apoptotic markers cleaved caspase-3 and poly ADP ribose polymerase. HO-3867 exhibited significant cytotoxicity toward ovarian cancer cells by inhibition of the JAK/STAT3 signaling pathway. The study suggested that HO-3867 may be useful as a safe and effective anticancer agent for ovarian cancer therapy.
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PMID:Anticancer efficacy of a difluorodiarylidenyl piperidone (HO-3867) in human ovarian cancer cells and tumor xenografts. 2044 15

1. Cardiotoxin (CTX) III, a basic polypeptide with 60 amino acid residues isolated from Naja naja atra venom, has potential anticancer therapeutic activity. The aim of the present study was to investigate the apoptotic effect (and the underlying mechanism of action) of CTX III in human adenocarcinoma A549 cells. 2. It was found that CTX III induces apoptosis in A549 cells, as indicated by an increase in the sub-G(1) population, phosphatidylserine externalization, loss of mitochondrial membrane potential (Psi(m)) with cytochrome c release and activation of caspases 9 and 3. These actions were correlated with upregulation of Bax and Bad and downregulation of various anti-apoptotic proteins, including Bcl-2, Bcl-X(L), Mcl-1, X-linked inhibitor of apoptosis protein (XIAP) and p-Bad in CTX III-treated cells. 3. The signal transduction pathways involved in the effects of CTX III in A549 cells were evaluated using 5 micromol/L AG1478, an inhibitor of the epidermal growth factor receptor (EGFR), and exposing cells to the drug for 8 h. The results indicated that CTX III suppresses phosphorylation of EGFR and activation of phosphatidylinositol 3-kinase (PI3-K)/Akt and Janus tyrosine kinase (JAK) 2/signal transducer and activator of transcription (STAT) 3, all of which are downstream molecules in the EGFR signalling pathway. 4. Exposure of cells for 8 h to the PI3-K inhibitor wortmannin (10 micromol/L) blocked JAK2 and STAT3 activation, whereas exposure of cells to the JAK2 inhibitor AG490 (5 micromol/L) decreased levels of phosphorylated (p-) JAK2 and p-STAT3 without affecting PI3-K/Akt activation. These observations suggest that PI3-K is an upstream activator of JAK2/STAT3. Furthermore, 5 micromol/L AG490 and 10 micromol/L wortmannin treatment of A549 cells for 8 h resulted in upregulation of Bax and Bad and downregulation of Bcl-2, Bcl-X(L), XIAP and p-Bad. 5. Together, the results of the present study indicate that CTX III induces apoptosis in A549 cells by inactivating the EGFR, PI3-K/Akt and JAK2/STAT3 signalling pathways.
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PMID:Concomitant inactivation of the epidermal growth factor receptor, phosphatidylinositol 3-kinase/Akt and Janus tyrosine kinase 2/signal transducer and activator of transcription 3 signalling pathways in cardiotoxin III-treated A549 cells. 2045 25

Cardiotoxin III (CTX III), a basic polypeptide with 60-amino acid residues isolated from Naja naja atra venom, has been reported to have cytotoxic activity. CTX III exerted cytotoxicity with the S-phase cell cycle arrest, correlated with a marked decrease in the expression levels of cyclin A, cyclin B, and cyclin-dependent kinase 1 (CDK1), and apoptosis, accompanied with Bax and Bad up-regulation, and the down-regulation of Bcl-2, p-Bad, and X-linked inhibitor of apoptosis (XIAP) with cytochrome c release and sequential activation of caspase-9 and caspase-3 in Ca9-22 cells. Mechanistic studies showed that CTX III suppressed the phosphorylation of Src, EGFR, STAT3, STAT5, Akt, and activation of PI3 K (p110). Moreover, Src inactivation was observed earlier than that of the EGFR and the Src inhibitor PP2 suppressed the levels of phospho-EGFR, phospho-STAT3, phospho-STAT5, phospho-Akt, and PI3 K(p110). The PP2 also caused the S-phase arrest and apoptosis, and led to down-regulation of Bcl-2, p-Bad, XIAP, cyclin A, cyclin B, and CDK1, and up-regulation of Bax and Bad, similar to that observed in CTX III treatment. Taken together, these results indicate that CTX III induces apoptosis and S-phase arrest in Ca9-22 cells via concomitant inactivation of the Src, EGFR, STAT3, STAT5, PI3 K(p110), and Akt signaling pathways.
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PMID:Taiwan cobra cardiotoxin III inhibits Src kinase leading to apoptosis and cell cycle arrest of oral squamous cell carcinoma Ca9-22 cells. 2049 3


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