Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Immunosuppressive therapy increases the risk of recurrence of initial cancers in organ transplant patients, and compelling therapeutic protocols are needed to suppress the malignancy and protect the allograft. We examined the potential use of 15-deoxyspergualin (DSG) in relation to organ transplantation and cancer. The effect of DSG on established liver metastatic tumors in recipient rats bearing a heart allograft was evaluated using an in vivo luminescent technique with luciferase-expressing RCN-H4 rat colon cancer cells. The inhibition of cell growth by DSG was correlated with NF-kappa B activity and caspase-3/7 activity in vitro. In the cyclosporine A (CsA)-induced cancer progression model of rats, DSG treatment (3 mg/kg) blocked the increase in tumor-derived luciferase activity, while CsA (15 mg/kg) facilitated luciferase activity up to around day 20 after cardiac transplantation. Our data suggest that DSG may be a therapeutic candidate for the control of tumor growth in transplant patients.
 ...
PMID:Control of cyclosporine A-induced tumor progression using 15-deoxyspergualin for rat cardiac transplantation. 1770 Jan 70

Pancreatic cancer is one of the most aggressive malignant diseases. We recently reported that N-cadherin plays a key role in tumor progression and metastasis in pancreatic cancer. For this study, we sought to determine if an N-cadherin-blocking peptide (ADH-1) could prevent N-cadherin-mediated tumor progression in a mouse model for pancreatic cancer. The effect of ADH-1 on N-cadherin-mediated cell scattering and migration on collagen I was examined using pancreatic cancer cells. We also examined the influence of ADH-1 on cell apoptosis. Furthermore, in vivo animal studies were performed using orthotopic injection of N-cadherin overexpressing BxPC-3 cells with or without ADH-1 treatment. BxPC-3 and Capan-1 cells exhibited increased expression of N-cadherin in response to collagen I. This increase in N-cadherin promoted cell scattering and migration in response to collagen I. ADH-1 prevented these changes, but did not inhibit upregulation of N-cadherin. TUNEL assays and immunoblots for caspase-3 showed that ADH-1 induced apoptosis in a concentration dependent and N-cadherin dependent manner in pancreatic cancer cells. ADH-1 treatment resulted in significant reductions in tumor growth and lung metastasis in a mouse model for pancreatic cancer. The N-cadherin antagonist, ADH-1 has significant antitumor activity against N-cadherin-expressing cells using in vitro assays and in an orthotopic mouse model for pancreatic cancer, raising the possibility that N-cadherin antagonists have therapeutic potential for the treatment of pancreatic cancer in humans.
 ...
PMID:ADH-1 suppresses N-cadherin-dependent pancreatic cancer progression. 1772 21

An angiogenic factor, thymidine phosphorylase (TP), confers resistance to apoptosis induced by hypoxia. We investigated the molecular basis for the suppressive effect of TP on hypoxia-induced apoptosis using Jurkat cells transfected with TP cDNA, Jurkat/TP, and a mock transfectant, Jurkat/CV. TP and 2-deoxy-d-ribose, a degradation product of thymidine generated by TP enzymatic activity, suppressed hypoxia-induced apoptosis. They also inhibited the upregulation of hypoxia-inducible factor (HIF) 1alpha and the proapoptotic factor, BNIP3, and caspase 3 activation induced by hypoxia. Introduction of siRNA against BNIP3 in Jurkat cells decreased the proportion of apoptotic cells under hypoxic condition. These findings suggest that the suppression of BNIP3 expression by TP prevents, at least in part, hypoxia-induced apoptosis. Expression levels of TP are elevated in many malignant solid tumors and thus 2-deoxy-d-ribose generated by TP in these tumors might play an important role in tumor progression by preventing hypoxia-induced apoptosis.
 ...
PMID:Thymidine phosphorylase inhibits the expression of proapoptotic protein BNIP3. 1835 86

Several micronutrients present in fruits and vegetables exhibit anticancer activity as a result of their actions on molecular targets involved in carcinogenesis and tumor progression. Curcumin, a phenolic phytochemical derived from the rhizome of Curcuma longa, exhibits both cancer-preventative activity and growth inhibitory effects on neoplastic cells. Several studies report that curcumin inhibits cancer cell proliferation and induces apoptosis in cancer cells through p21-mediated cell cycle arrest. Cancer cells that are deficient in p21 are also reported to be more prone to undergo apoptosis in response to a variety of cytotoxic agents. In this study, we determined whether curcumin-induced cytotoxicity in cultures of HCT-116 human colon cancer cells was dependent on p21 status. Curcumin killed wild-type HCT-116 cells in a dose- and time-dependent manner, as measured in an MTT cell viability assay. Moreover, an equivalent cytotoxic effect by curcumin was observed in both p21(+/+) and p21(-/-)HCT-116 cells, indicating that curcumin-induced cytotoxicity was p21-independent. Primary cultures of human dermal fibroblasts were less sensitive than HCT-116 colon cancer cells to lower doses of curcumin, suggesting a degree of selectivity for neoplastic cells. Western blot analysis showed that cell death in curcumin-treated cultures of p21(+/+) and p21(-/-) HCT-116 cells was associated with a reduction in pro-caspase-3 and PARP-1 cleavage, which are indicative of apoptosis. We conclude that curcumin-induced apoptosis in HCT-116 colon cancer cells does not depend on p21 status.
 ...
PMID:Curcumin induces apoptosis in HCT-116 human colon cancer cells in a p21-independent manner. 1842 3

Brahma-related gene 1 (BRG1) is a catalytic subunit of the switch in mating type/sucrose nonfermentation complex and plays an important role in cancer development. Mouse homozygous knockout experiments testing the role of BRG1 in tumorigenesis have been hampered because BRG1 inactivation is embryonic lethal. To bypass this constraint, we developed a lung-specific conditional knockout of BRG1 and examined the effect of BRG1 inactivation in an ethyl carbamate lung carcinogenesis mouse model. We found that the heterozygous loss of BRG1 resulted in increases in both the number and size of tumors when compared with controls. In contrast, when both BRG1 alleles were inactivated, neither the number nor the size of tumors increased compared with controls. In mouse lung tissue where BRG1 was homozygously inactivated, immunostaining for apoptotic markers showed significant increase in Apo-BrdUrd and cleaved caspase-3. These data indicate that a loss of cell viability underlies why biallelic inactivation of BRG1 does not increase tumorigenesis. We also examined mice when exposed to the carcinogen ethyl carbamate and then subjected to BRG1 inactivation. In these cells, loss of BRG1 after carcinogen exposure potentiated tumor development. A subset of tumors retained BRG1 expression, whereas others showed either partial or complete loss of BRG1 expression. Tumors completely devoid of BRG1 expression were significantly larger and expressed higher levels of two markers of proliferation, proliferating cell nuclear antigen and Ki67. Although biallelic inactivation of BRG1 could not initiate tumor development in untransformed cells, our results indicate that transformation and tumor progression are greatly affected by loss of BRG1.
 ...
PMID:Targeted knockout of BRG1 potentiates lung cancer development. 1848 51

The process of cell dissemination from the primary tumors to distant sites is the most harmful event during cancer progression, and the leading cause of cancer death. We have previously demonstrated that restoration of DLC1 tumor suppressor gene expression in the DLC1-negative Focus and 7703K human hepatocellular carcinoma (HCC) cell lines induced caspase-3 mediated apoptosis, reduced cell growth in vitro and tumorigenicity in vivo and diminished the ability to migrate through Matrigel, a property suggestive of metastatic potential in vivo. We now show that subcutaneous tumors developing after inoculation of Focus and 7703K cells into nude mice disseminate cells to liver and lung, and this process is markedly suppressed by restoration of DLC1 expression. Inhibition of tumor cell dissemination was associated with lower levels of RhoA activity, an increase in rounded cells and a reduction in actin stress fibers and focal adhesion molecules that are of critical importance in cancer cell invasion and metastasis. In addition, DLC1 down-regulated the expression of osteopontin and matrix metalloproteinase-9, which are highly up-regulated in most primary HCC with associated metastases. These observations implicate the DLC1 gene in suppression of HCC cell dissemination and identify novel cellular and genetic alterations that contribute to prevention of metastasis, a life-threatening event in cancer progression.
 ...
PMID:DLC1 suppresses distant dissemination of human hepatocellular carcinoma cells in nude mice through reduction of RhoA GTPase activity, actin cytoskeletal disruption and down-regulation of genes involved in metastasis. 1849 90

Metallothioneins (MTs) are a family of low molecular weight proteins with a high affinity for divalent metals. Metallothionein has been shown to have a protective role in apoptosis. Specifically, it controls the cellular zinc ion levels. The proper intracellular Zn2+ level maintains the fragmentation of DNA associated with caspase-3 activity. In cancer nests, MT has been identified in the peripheral regions and associated with higher cell proliferation rates and fewer positive apoptotic cells. The expression of MT in the stroma has been linked with tumor spread. The tumor stroma may respond to tumor growth and aggressiveness by the expression of MT, thus protecting itself from and developing a resistance to apoptosis. Multistep carcinogenesis is related to a breakdown in immune response that enables tumor progression and dissemination. This breakdown is a crucial for tumor survival. The evaluation of MT expression in cancer and its stroma seems to correlate with the level of immune system inhibition in cancer-adjacent stroma.
 ...
PMID:The possible biological role of metallothionein in apoptosis. 1850 97

Tumor cells induce excessive osteoclastogenesis, mediating pathologic bone resorption and subsequent release of growth factors and calcium from bone matrix, resulting in a "vicious cycle" of bone breakdown and tumor proliferation. RANK ligand (RANKL) is an essential mediator of osteoclast formation, function, and survival. In metastatic prostate cancer models, RANKL inhibition directly prevents osteolysis via blockade of osteoclastogenesis and indirectly reduces progression of skeletal tumor burden by reducing local growth factor and calcium concentrations. Docetaxel, a well-established chemotherapy for metastatic hormone-refractory prostate cancer, arrests the cell cycle and induces apoptosis of tumor cells. Suppression of osteoclastogenesis through RANKL inhibition may enhance the effects of docetaxel on skeletal tumors. We evaluated the combination of the RANKL inhibitor osteoprotegerin-Fc (OPG-Fc) with docetaxel in a murine model of prostate cancer bone metastasis. Tumor progression, tumor area, and tumor proliferation and apoptosis were assessed. OPG-Fc alone reduced bone resorption (P < 0.001 versus PBS), inhibited progression of established osteolytic lesions, and reduced tumor area (P < 0.0001 versus PBS). Docetaxel alone reduced tumor burden (P < 0.0001 versus PBS) and delayed the development of osteolytic lesions. OPG-Fc in combination with docetaxel suppressed skeletal tumor burden (P = 0.0005) and increased median survival time by 16.7% (P = 0.0385) compared with docetaxel alone. RANKL inhibition may enhance docetaxel effects by increasing tumor cell apoptosis as evident by increased active caspase-3. These studies show that inhibition of RANKL provides an additive benefit to docetaxel treatment in a murine model of prostate cancer bone metastasis and supports clinical evaluation of this treatment option in patients.
 ...
PMID:RANK ligand inhibition plus docetaxel improves survival and reduces tumor burden in a murine model of prostate cancer bone metastasis. 1860 16

Matrix Metalloproteinase-9 (MMP-9) consists of a prodomain, catalytic domain with 3 fibronectin-like type II modules and C-terminal hemopexin-like (PEX) domain. These domains play distinct roles in terms of proteolytic activity, substrate binding and interaction with inhibitors and receptors. To assess the potential of the MMP-9-PEX domain to interfere with tumor progression, we stably transfected human glioblastoma cells with an expression vector containing a cDNA sequence of the MMP-9-PEX. The selected clones exhibited decreased MMP-9 activity and reduced invasive capacity. We assessed how secretion of MMP-9-PEX by glioblastoma cells affects angiogenic capabilities of human microvascular endothelial cells (HMECs) in vitro. MMP-9-PEX conditioned medium treatment caused a reduction in migration of HMECs and inhibited capillary-like structure formation in association with suppression of vascular endothelial growth factor (VEGF) secretion and VEGF receptor-2 protein level. The suppression of HMECs survival by conditioned medium from MMP-9-PEX stable transfectants was associated with apoptosis induction characterized by an increase in cells with a sub-G0/G1 content, fragmentation of DNA, caspase-3, -8 and -9 activation and poly (ADP-ribose) polymerase (PARP) cleavage. A significant tumor growth inhibition was observed in intracranial implants of MMP-9-PEX stable transfectants in nude mice with attenuation of CD31 and MMP-9 protein expression. These results demonstrate that MMP-9-PEX inhibits angiogenic features of endothelial cells and retards intracranial glioblastoma growth.
 ...
PMID:The hemopexin domain of MMP-9 inhibits angiogenesis and retards the growth of intracranial glioblastoma xenograft in nude mice. 1894 17

Effective treatment of malignant melanoma with the tumor-selective death ligand tumor necrosis-related apoptosis-inducing ligand (TRAIL) is curtailed by the fact that many melanoma cell lines are a priori resistant against TRAIL-induced apoptosis. By investigating 18 melanoma cell lines, we show that TRAIL susceptibility is completely independent of the tumor progression stage but can be positively stimulated by co-exposure to a sublethal ultraviolet B light (UVB) dose, providing an excellent tool to study the mechanism underlying TRAIL resistance. TRAIL resistance could be linked to the ratio of x-linked inhibitor of apoptosis proteins (xIAP) and caspase-3 levels within the cell. UVB-induced sensitization coincides with enhanced xIAP degradation, allowing full caspase-3 processing and activation. It is also accompanied by concomitant IkappaBalpha degradation, resulting in nuclear factor-kappaB (NF-kappaB)-dependent transcriptional repression of xIAP. Loss of xIAP in turn was reduced upon overexpression of an IkappaBalpha super-repressor, thus NF-kappaB activation seems to be responsible for differential regulation of xIAP and consequently determines TRAIL susceptibility. As xIAP-mediated blockade of apoptosis seems to be the dominant cause of TRAIL resistance of all melanoma cell lines investigated here, our data suggest that direct chemical xIAP inhibition or combination treatment with DNA-damaging agents may offer new therapeutic strategies to generally sensitize melanoma toward TRAIL-induced apoptosis.
 ...
PMID:Sensitization of melanoma cells to TRAIL by UVB-induced and NF-kappaB-mediated downregulation of xIAP. 1897 16


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>