Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.B10 (caspase-7)
 896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Elevated expression or activity of the transcription factor forkhead box M1 (FOXM1) is associated with the development and progression of many malignancies, including breast cancer. In this study, we show that the thiazole antibiotic thiostrepton selectively induces cell cycle arrest and cell death in breast cancer cells through down-regulating FOXM1 expression. Crucially, our data show that thiostrepton treatment reduced FOXM1 expression in a time- and dose-dependent manner, independent of de novo protein synthesis and predominantly at transcriptional and gene promoter levels. Our results indicate that thiostrepton can induce cell death through caspase-dependent intrinsic and extrinsic apoptotic pathways as well as through caspase-independent death mechanisms, as observed in MCF-7 cells, which are deficient of caspase-3 and caspase-7. Cell cycle analysis showed that thiostrepton induced cell cycle arrest at G(1) and S phases and cell death, concomitant with FOXM1 repression in breast cancer cells. Furthermore, thiostrepton also shows efficacy in repressing breast cancer cell migration, metastasis, and transformation, which are all downstream functional attributes of FOXM1. We also show that overexpression of a constitutively active FOXM1 mutant, DeltaN-FOXM1, can abrogate the antiproliferative effects of thiostrepton. Interestingly, thiostrepton has no affect on FOXM1 expression and proliferation of the untransformed MCF-10A breast epithelial cells. Collectively, our data show that FOXM1 is one of the primary cellular targets of thiostrepton in breast cancer cells and that thiostrepton may represent a novel lead compound for targeted therapy of breast cancer with minimal toxicity against noncancer cells.
Mol Cancer Ther 2008 Jul
PMID:Thiostrepton selectively targets breast cancer cells through inhibition of forkhead box M1 expression. 1864 12

Androgen receptor (AR) is the main therapeutic target for treatment of metastatic prostate cancers (PCa). As recurrent tumors restore AR activity independent of hormones, new therapies that abolish AR activity have been sought to prevent or delay the emergence of ablation-resistant disease. Here, we report that a novel abietane diterpene, 6-hydroxy-5,6-dehydrosugiol (HDHS), isolated from the stem bark of Cryptomeria japonica, was a potent AR antagonist in PCa cells. HDHS treatment of androgen-dependent LNCaP and androgen-responsive 22Rv1 cells induced apoptosis as shown by nucleosome release, activation of caspase-3 and caspase-7, and cleavage of poly(ADP-ribose) polymerase accompanied with concomitant up-regulation of tumor suppressor p53. HDHS also decreased the protein expression of cyclins (D1 and E), cyclin-dependent kinases (CDK2, CDK4, and CDK6), and retinoblastoma phosphorylation in PCa cells, which suggest cell cycle arrest in the G(1) phase. Oral administration of HDHS at 0.5 and 2.5 mg/kg once daily for 24 days to 22Rv1 PCa xenografted mice suppressed tumor growth by 22% and 39%, respectively, in association with decreased proliferation and increased apoptosis in tumor cells, which further correlated with increased levels of HDHS in plasma and tumors. Overall, our data suggest that HDHS has potential for use in chemoprevention and chemotherapy of PCa.
Cancer Res 2008 Aug 15
PMID:A novel diterpene suppresses CWR22Rv1 tumor growth in vivo through antiproliferation and proapoptosis. 1870 87

During development inhibitor of DNA-bind-2 (Id2) regulates proliferation and differentiation. Id2 expression has been detected in cancer cells, yet its cellular function and validity as a therapeutic target remains largely unknown. Immunohistochemical analysis of colorectal cancer (CRC) specimens revealed that Id2 was undetectable in normal colonic mucosa, but occurs in 40% of primary tumors and in most CRC liver metastases (P<0.0001). Additionally, Id2 was expressed in all CRC cell lines assayed. CRC cells with reduced Id2 expression demonstrated reduced proliferation. Analysis of CRC cell cycle regulatory proteins showed that reducing Id2 levels reduces cyclin D1 levels and increased p21 levels. Reduction of Id2 expression also enhanced tumor cell apoptosis, increasing levels of the pro-apoptotic protein Bim/Bod, and cleavage of caspase-7 and poly (ADP-ribose) polymerase. In vivo studies show tumors derived from cells with decreased Id2 levels formed smaller tumors with fewer metastases compared with tumors with normal levels (P<0.05). Furthermore, intraperitoneal administration of Id2 small interfering RNA (siRNA) conjugated with the neutral liposome 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine decreased tumor burden in mice compared with control treatment (P=0.006). We conclude that Id2 is upregulated in CRC, and is important in promoting cell survival. In vivo targeting of Id2 by siRNA establishes that it is a valid therapeutic target where its expression occurs.
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PMID:Therapeutic targeting of Id2 reduces growth of human colorectal carcinoma in the murine liver. 3236 6

Calcitriol actions are mediated by the vitamin D receptor (VDR), a nuclear transcription factor of the steroid-retinoid-thyroid nuclear receptor gene superfamily. Calcitriol inhibits the growth of many cells including cancer cells by inducing cell cycle arrest. In some cancer cell lines, calcitriol also induces apoptosis. In the LNCaP prostate cancer cell line, induction of apoptosis and caspase-3/7 activities by staurosporine (STS) abolished [(3)H]1,25-dihydroxy vitamin D(3) binding and VDR protein, suggesting that the VDR may be targeted for inactivation by caspases during apoptosis. A potential caspase-3 site (D(195)MMD(198)S) was identified in the human VDR ligand-binding domain. Mutations D195A, D198A, and S199A were generated in the putative capase-3 cleavage site. In transfected COS-7 cells, STS treatment resulted in the cleavage of the wild-type (WT) VDR and S199A mutant VDR but not the D195A or D198A mutants. In in vitro assays, the WT VDR and S199A mutant VDR were cleaved by caspase-3, although the D195A and D198A mutants were resistant to caspase-3. In vitro, the WT VDR was also cleaved by caspase-6 and caspase-7 and in extracts of STS-treated LNCaP cells. In STS-treated LNCaP cells and human skin fibroblasts, the proteasome inhibitor MG-132 protected the VDR caspase cleavage fragment from further degradation by the 26S proteasome. The rat VDR that does not contain the caspase-3 cleavage site was not cleaved in STS-treated COS-7 cells. In conclusion, our results demonstrate that the human VDR is a target of caspase-3 and suggest that activation of caspase-3 may limit VDR activity.
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PMID:Inactivation of the human vitamin D receptor by caspase-3. 1883 97

HL-37, a novel anthracene derivative, exhibited potent anticancer activity in many kinds of cancer cells. However, the exact mechanism and signaling pathway involved in HL-37-induced apoptosis have not been fully elucidated. Therefore, we explored the mechanisms of HL-37-mediated apoptosis in MCF-7 and MDA-MB-435 human breast cancer cells. When MCF-7 cells or MDA-MB-435 cells were co-incubated with HL-37, the percentage of apoptotic cell and S phase of cell cycle was markedly increased. In addition, a rise in intracellular calcium levels, ROS production, phosphorylation of JNK and activation of calpain were found in both MCF-7 cells and MDA-MB-435 cells after exposure to HL-37. With the HL-37-mediated reduction of mitochondrial membrane potential, cytochrome c was released from mitochondria to cytosol. Moreover, HL-37 strongly induced cleavage of caspase-4, caspase-9, as well as caspase-3 in MDA-MB-435 cells, whereas, activation of caspase-4, caspase-9 and caspase-7 but not caspase-3 was detected in MCF-7 cells. These results suggested that HL-37 induced MDA-MB-435 and MCF-7 cells apoptosis via oxidative stress and Ca(2+)/calpain/caspase-4 pathway.
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PMID:HL-37, a novel anthracene derivative, induces Ca(2+)-mediated apoptosis in human breast cancer cells. 1894 64

Previous studies have demonstrated that gamma-synuclein is overexpressed in a variety of human malignancies. Overexpression of gamma-synuclein in human breast cancer cells leads to an increase in cell motility, resistance to chemotherapeutic drugs, and mitotic checkpoint dysfunction. We report in this study that gamma-synuclein is up-regulated by endoplasmic reticulum stress. The up-regulation of gamma-synuclein expression by endoplasmic reticulum stress is mediated, at least in part, by activation transcription factor (ATF) 4. Knockdown of gamma-synuclein sensitized human breast cancer cells to endoplasmic reticulum stress-induced apoptosis. Induction of apoptosis by endoplasmic reticulum stress when gamma-synuclein was inhibited was dependent on JNK or caspase activation, with caspase-3 and caspase-7 being involved. Treatment with the JNK or caspase-3 and caspase-7 inhibitor partially blocked endoplasmic reticulum stress-induced apoptosis in breast cancer cells transfected with or without the siRNA against gamma-synuclein. Taken together, these data suggest that gamma-synuclein may promote cancer progression by suppressing endoplasmic reticulum stress-induced apoptosis.
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PMID:Up-regulation of gamma-synuclein contributes to cancer cell survival under endoplasmic reticulum stress. 1900 86

We have previously shown in separate studies that MDM2 knockdown via antisense MDM2 (AS-MDM2) and E2F1 overexpression via adenoviral-mediated E2F1 (Ad-E2F1) sensitized prostate cancer cells to radiation. Because E2F1 and MDM2 affect apoptosis through both common and independent pathways, we hypothesized that coupling these two treatments would result in increased killing of prostate cancer cells. In this study, the effect of Ad-E2F1 and AS-MDM2 in combination with radiation was investigated in three prostate cancer cell lines: LNCaP cells, LNCaP-Res cells [androgen insensitive with functional p53 and androgen receptor (AR)], and PC3 cells (androgen insensitive, p53(null), and AR(null)). A supra-additive radiosensitizing effect was observed in terms of clonogenic inhibition and induction of apoptosis (caspase-3 + caspase-7 activity) in response to Ad-E2F1 plus AS-MDM2 treatments in all three cell lines. In LNCaP and LNCaP-Res, these combination treatments elevated the levels of phospho-Ser(15) p53 with significant induction of p21(waf1/cip1), phospho-gammaH2AX, PUMA, and Bax levels and reduction of AR and bcl-2 expression. Similarly, AR(null) and p53(null) PC-3 cells showed elevated levels of Bax and phospho-gammaH2AX expression. These findings show that the combination of Ad-E2F1 and AS-MDM2 significantly increases cell death in prostate cancer cells exposed to radiation and that this effect occurs in the presence or absence of AR and p53.
Mol Cancer Res 2008 Nov
PMID:Antisense MDM2 enhances E2F1-induced apoptosis and the combination sensitizes androgen-sensitive [corrected] and androgen-insensitive [corrected] prostate cancer cells to radiation. 1901 Aug 21

The EphA2 receptor tyrosine kinase is selectively expressed on the surface of many different human tumors. We have previously shown that tumor cells can be targeted by EphA2 monoclonal antibodies and that these antibodies function, in part, by inducing EphA2 internalization and degradation. In this report, we describe the isolation and characterization of a fully human monoclonal antibody (1C1) that selectively binds both the human and rodent EphA2 receptor. After cell binding, the antibody induces rapid tyrosine phosphorylation, internalization, and degradation of the EphA2 receptor. Because monoclonal antibodies that selectively bind tumor cells and internalize provide a vehicle for targeted delivery of cytotoxics, 1C1 was conjugated to the microtubule inhibitor monomethylauristatin phenylalanine using a stable maleimidocaproyl linker. The anti-EphA2 antibody-drug conjugate [1C1-maleimidocaproyl-MMAF (mcMMAF)] stimulated the activation of caspase-3/caspase-7 and the death of EphA2-expressing cells with IC(50) values as low as 3 ng/mL. Similarly, the conjugate induced degradation of the EphA2 receptor and inhibited tumor growth in vivo. Administration of 1C1-mcMMAF at doses as low as 1 mg/kg once weekly resulted in significant growth inhibition of EphA2-expressing tumors without any observable adverse effects in mouse xenograft and rat syngeneic tumor models. Our data support the use of an antibody-drug conjugate approach to selectively target and inhibit the growth of EphA2-expressing tumors.
Cancer Res 2008 Nov 15
PMID:A human antibody-drug conjugate targeting EphA2 inhibits tumor growth in vivo. 1901 Sep 11

The anticancer potency of green tea and its individual components is being intensely investigated, and some cancer patients already self-medicate with this "miracle herb" in hopes of augmenting the anticancer outcome of their chemotherapy. Bortezomib (BZM) is a proteasome inhibitor in clinical use for multiple myeloma. Here, we investigated whether the combination of these compounds would yield increased antitumor efficacy in multiple myeloma and glioblastoma cell lines in vitro and in vivo. Unexpectedly, we discovered that various green tea constituents, in particular (-)-epigallocatechin gallate (EGCG) and other polyphenols with 1,2-benzenediol moieties, effectively prevented tumor cell death induced by BZM in vitro and in vivo. This pronounced antagonistic function of EGCG was evident only with boronic acid-based proteasome inhibitors (BZM, MG-262, PS-IX), but not with several non-boronic acid proteasome inhibitors (MG-132, PS-I, nelfinavir). EGCG directly reacted with BZM and blocked its proteasome inhibitory function; as a consequence, BZM could not trigger endoplasmic reticulum stress or caspase-7 activation, and did not induce tumor cell death. Taken together, our results indicate that green tea polyphenols may have the potential to negate the therapeutic efficacy of BZM and suggest that consumption of green tea products may be contraindicated during cancer therapy with BZM.
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PMID:Green tea polyphenols block the anticancer effects of bortezomib and other boronic acid-based proteasome inhibitors. 1974 81

In spite of compelling evidence-implicating caspases in drug-induced apoptosis, how tumors modulate caspase expression and activity to overcome the cytotoxicity of anticancer agents is not fully understood. To address this issue, we investigated the role of caspases-3 and caspase-7 in determining the response of breast and lung tumor cell lines to chemotherapy. We found that an early and late apoptotic response correlated with weak and strong cellular caspase-activation, respectively. The results highlight an underappreciated relationship of temporal apoptotic response with caspase-activation and drug resistance. Moreover, the extent of tumor growth restoration after drug withdrawal was dependent on the degree of endogenous blockage of caspase-3 and caspase-7 cleavages. This points to an unrecognized role of caspase modulation in tumor recurrence and suggests that targeting caspase cleavage is a rational approach to increasing potency of cancer drugs.
Cancer Invest 2009 May
PMID:Modulation of effector caspase cleavage determines response of breast and lung tumor cell lines to chemotherapy. 1924 Nov 92


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