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: UMLS:C0009402 (colorectal cancer)
53,228 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The expression of DCC (deleted in colorectal cancer) is often markedly reduced in colorectal and other cancers. However, the rarity of point mutations identified in DCC coding sequences and the lack of a tumor predisposition phenotype in DCC hemizygous mice have raised questions about its role as a tumor suppressor. DCC also mediates axon guidance and functions as a dependence receptor; such receptors create cellular states of dependence on their respective ligands by inducing apoptosis when unoccupied by ligand. We now show that DCC drives cell death independently of both the mitochondria-dependent pathway and the death receptor/caspase-8 pathway. Moreover, we demonstrate that DCC interacts with both caspase-3 and caspase-9 and drives the activation of caspase-3 through caspase-9 without a requirement for cytochrome c or Apaf-1. Hence, DCC defines an additional pathway for the apoptosome-independent caspase activation.
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PMID:The dependence receptor DCC (deleted in colorectal cancer) defines an alternative mechanism for caspase activation. 1124 93

We have constructed a replication-deficient adenovirus encoding a nonphosphorylatable Thr(34)-->Ala mutant of the apoptosis inhibitor survivin (pAd-T34A) to target tumor cell viability in vitro and in vivo. Infection with pAd-T34A caused spontaneous apoptosis in cell lines of breast, cervical, prostate, lung, and colorectal cancer. In contrast, pAd-T34A did not affect cell viability of proliferating normal human cells, including fibroblasts, endothelium, or smooth muscle cells. Infection of tumor cells with pAd-T34A resulted in cytochrome c release from mitochondria, cleavage of approximately 46-kDa upstream caspase-9, processing of caspase-3 to the active subunits of approximately 17 and 19 kDa, and increased caspase-3 catalytic activity. When compared with chemotherapeutic regimens, pAd-T34A was as effective as taxol and considerably more effective than adriamycin in induction of tumor cell apoptosis and enhanced taxol-induced cell death. In three xenograft breast cancer models in immunodeficient mice, pAd-T34A suppressed de novo tumor formation, inhibited by approximately 40% the growth of established tumors, and reduced intraperitoneal tumor dissemination. Tumors injected with pAd-T34A exhibited loss of proliferating cells and massive apoptosis by in situ internucleosomal DNA fragmentation. These data suggest that adenoviral targeting of the survivin pathway may provide a novel approach for selective cancer gene therapy.
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PMID:Cancer gene therapy using a survivin mutant adenovirus. 1180 41

The cornerstone of the systemic treatment of advanced colorectal cancer is 5-fluorouracil.However, 5-fluorouracil-induced apoptosis is dependent on p53, a tumor suppressor gene that is lost or inactivated in at least 85% of human colorectal cancers. Here we show that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo2L triggers caspase-8-mediated truncation of BID, mitochondrial activation of caspase-9, and apoptosis in both p53(+/+) or p53(-/-) isogenic HCT116 colorectal cancer cells. TRAIL/Apo2L also sensitizes both p53(+/+) or p53(-/-) colorectal cancer cells to ionizing radiation. In contrast, we find that TRAIL/Apo2L fails to activate caspase-9 or induce apoptosis in isogenic HCT116 colorectal cancer cells that are deficient in BAX, a proapoptotic gene that is mutated in >50% of colorectal cancers of the microsatellite mutator phenotype. Loss of BAX also renders colorectal cancer cells resistant to TRAIL/Apo2L-mediated radiosensitization. We additionally demonstrate that TRAIL/Apo2L-induced death of p53(+/+)- or p53(-/-)- BAX-proficient but not BAX-deficient colorectal cancer cells is augmented by reducing nuclear factor-kappaB-dependent expression of Bcl-x(L) with either a peptide that disrupts the inhibitor of kappaB kinase complex or the nonsteroidal anti-inflammatory drug, sulindac sulfide. These results indicate that the combination of TRAIL/Apo2L with either irradiation or sulindac may be highly effective against both p53-proficient and p53-deficient colorectal cancers; however, BAX-deficient tumors may evade elimination by TRAIL/Apo2L-based regimens. Our findings may aid the development and genotype-specific application of TRAIL/Apo2L-based combinatorial regimens for the treatment of colorectal cancers.
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PMID:Requirement of BAX for TRAIL/Apo2L-induced apoptosis of colorectal cancers: synergism with sulindac-mediated inhibition of Bcl-x(L). 1191 24

Activation of Ras promotes oncogenesis by altering a multiple of cellular processes, such as cell cycle progression, differentiation, and apoptosis. Oncogenic Ras can either promote or inhibit apoptosis, depending on the cell type and the nature of the apoptotic stimuli. The response of normal and transformed colonic epithelial cells to the short chain fatty acid butyrate, a physiological regulator of epithelial cell maturation, is also divergent: normal epithelial cells proliferate, and transformed cells undergo apoptosis in response to butyrate. To investigate the role of k-ras mutations in butyrate-induced apoptosis, we utilized HCT116 cells, which harbor an oncogenic k-ras mutation and two isogenic clones with targeted inactivation of the mutant k-ras allele, Hkh2, and Hke-3. We demonstrated that the targeted deletion of the mutant k-ras allele is sufficient to protect epithelial cells from butyrate-induced apoptosis. Consistent with this, we showed that apigenin, a dietary flavonoid that has been shown to inhibit Ras signaling and to reverse transformation of cancer cell lines, prevented butyrate-induced apoptosis in HCT116 cells. To investigate the mechanism whereby activated k-ras sensitizes colonic cells to butyrate, we performed a genome-wide analysis of Ras target genes in the isogenic cell lines HCT116, Hkh2, and Hke-3. The gene exhibiting the greatest down-regulation by the activating k-ras mutation was gelsolin, an actin-binding protein whose expression is frequently reduced or absent in colorectal cancer cell lines and primary tumors. We demonstrated that silencing of gelsolin expression by small interfering RNA sensitized cells to butyrate-induced apoptosis through amplification of the activation of caspase-9 and caspase-7. These data therefore demonstrate that gelsolin protects cells from butyrate-induced apoptosis and suggest that Ras promotes apoptosis, at least in part, through its ability to down-regulate the expression of gelsolin.
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PMID:Oncogenic Ras promotes butyrate-induced apoptosis through inhibition of gelsolin expression. 1521 23

Cancer cells frequently possess defects in the genetic and biochemical pathways of apoptosis. Members of the Bcl-2 family play pivotal roles in regulating apoptosis and possess at least one of four Bcl-2 homology (BH) domains, designated BH1 to BH4. The BH3 domain is the only one conserved in proapoptotic BH3-only proteins and plays an important role in protein-protein interactions in apoptosis by regulating homodimerization and heterodimerization of the Bcl-2 family members. To date, 10 BH3-only proapoptotic proteins have been identified and characterized in the human genome. The completion of the Human Genome Project and the availability of various public databases and sequence analysis algorithms allowed us to use the bioinformatic database-mining approach to identify one novel BH3-only protein, apolipoprotein L6 (ApoL6). The full-length cDNA of ApoL6 was identified, cloned, and functionally expressed in p53-null colorectal cancer cells (DLD-1). We found that overexpression of wild-type ApoL6 induced mitochondria-mediated apoptosis in DLD-1 cells characterized by release of cytochrome c and Smac/DIABLO from mitochondria and activation of caspase-9, whereas ApoL6 BH3 domain deletion allele did not. In addition, overexpression of ApoL6 also induced activation of caspase-8. Furthermore, we showed that adenovirus harboring the full-length cDNA of ApoL6 induced marked apoptosis in a variety of cancer cell types, and ApoL6 recruited and interacted with lipid/fatty acid components during the induction of apoptosis. To our knowledge, this is the first example that intracellular overproduction of an apolipoprotein induces marked apoptosis.
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PMID:Apolipoprotein l6, a novel proapoptotic Bcl-2 homology 3-only protein, induces mitochondria-mediated apoptosis in cancer cells. 1567 Dec 46

The natural product justicidin A, an arylnaphthalide lignan isolated from Justicia procumbens, significantly inhibited the growth of human colorectal cancer cells HT-29 and HCT 116 at day 6 post-treatment. Further study revealed that justicidin A-treated HT-29 and HCT 116 colorectal cancer cells died of apoptosis. Justicidin A treatment caused DNA fragmentation and an increase in phosphatidylserine exposure of the cells. The number of cells in the sub-G1 phase was also increased upon justicidin A treatment. Caspase-9 but not caspase-8 was activated, suggesting that justicidin A treatment damaged mitochondria. The mitochondrial membrane potential was altered and cytochrome c and Smac were released from mitochondria to the cytoplasm upon justicidin A treatment. The level of Ku70 in the cytoplasm was decreased, but that of Bax in mitochondria was increased by justicidin A. Since Ku70 normally binds and sequesters Bax, these results suggest that justicidin A decreases the level of Ku70 leading to translocation of Bax from the cytosol to mitochondria to induce apoptosis. Oral administration of justicidin A was shown to suppress the growth of HT-29 cells transplanted into NOD-SCID mice, suggesting chemotherapeutic potential of justicidin A on colorectal cancer cells.
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PMID:Justicidin A decreases the level of cytosolic Ku70 leading to apoptosis in human colorectal cancer cells. 1590 97

Specific ligands of the peripheral benzodiazepine receptor (PBR) have been shown to induce apoptosis in gastrointestinal cancers. The aim of this study was to characterize the signaling pathways of PBR ligand-induced apoptosis. FGIN-1-27 but not PK 11195-induced apoptosis was associated with a decrease of mitochondrial membrane potential and an increase of mitochondrial volume in HT29 colorectal cancer cells. However, PK 11195-elicited apoptosis was associated with a downregulation of Bcl-2, translocation of Bax to the mitochondria including subsequent oligomerization, and activation of caspase-9, indicating the involvement of mitochondria in PK 11195-induced apoptosis. Moreover, PK 11195-induced apoptosis was associated with the generation of reactive oxygen species. This study demonstrates a novel mechanism of PK 11195-induced mitochondrial apoptosis without alteration of the mitochondrial membrane potential. The characterization of signaling pathways associated with PBR ligand-induced apoptosis will build the base for a future use of these ligands in anti-neoplastic therapeutic approaches.
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PMID:Mechanisms of mitochondrial apoptosis induced by peripheral benzodiazepine receptor ligands in human colorectal cancer cells. 1590 3

Activation of p53 tumor suppressor induces either cell cycle arrest or apoptosis through transcription-dependent and independent pathways; however, their relative roles in apoptosis induction and how these pathways are regulated remains elusive. Here, we report a unique role for glycogen synthesis kinase-3beta (GSK-3beta) in regulating p53 functions in human colorectal cancer cells. Pharmacologic modulation of GSK-3beta markedly impaired p53-dependent transactivation of targets including p21 and Puma but promoted p53-dependent conformational activation of Bax, resulting in cytochrome c release, loss of mitochondrial membrane potential, and caspase-9 processing. Thus, p53-mediated damage response is converted from cell cycle arrest to apoptosis following exposure to a variety of chemotherapeutic agents. We found that this effect is associated with the modulation of inhibitory Ser(9) phosphorylation of GSK-3beta but not with the activating tyrosine phosphorylation. We further show that the induction of apoptosis is through a direct mitochondrial pathway that requires Bax but not Puma. Our results underscore the importance of transcription-independent mechanism in p53-induced apoptosis and indicate that GSK-3beta plays distinct dual roles in regulating p53 pathways: promoting p53 transcriptional activity in the nucleus but suppressing p53-mediated direct apoptotic function at the mitochondria. Importantly, our data suggest that small-molecule inhibition of GSK-3beta might represent a novel approach for modulating chemotherapy.
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PMID:Pharmacologic modulation of glycogen synthase kinase-3beta promotes p53-dependent apoptosis through a direct Bax-mediated mitochondrial pathway in colorectal cancer cells. 1620 75

DCC (deleted in colorectal cancer) is a putative tumor suppressor gene whose expression is lost in numerous cancers. DCC also encodes the main receptor for the neuronal navigation cue netrin-1. It has been shown that DCC belongs to the so-called family of dependence receptors. Such receptors induce apoptosis when their ligand is absent, thus conferring a state of cellular dependence on ligand availability. We recently proposed that DCC is a tumor suppressor because it induces the death of tumor cells that grow in settings of ligand unavailability. Moreover, it seems that the DCC/netrin-1 pair may also regulate neuron survival during nervous system development. However, the mechanisms by which DCC triggers cell death are still unknown. We show here that the localization of DCC to lipid rafts is a prerequisite for its proapoptotic activity, both in immortalized cells and in primary neurons. The presence of DCC in lipid rafts probably allows the formation of an adequate submembrane complex, because the interaction of caspase-9 with DCC is inhibited by the disorganization of lipid rafts. Thus, dependence receptors may require lipid raft localization for cell death signaling.
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PMID:The dependence receptor DCC requires lipid raft localization for cell death signaling. 1653 96

Epidemiologic studies reported that the prevalence of hereditary non-polyposis colon cancer (HNPCC) in male is about 1.5-fold higher than that in female. Decreases in circulatory estradiol (E2) have been reported to downregulate the expression of E2 receptor (ER) and significantly increase the risk of colorectal cancer. Patients that received E2 replacement therapy were found to have a reduction in the incidence of colon adenoma and carcinoma. Furthermore, significant decreases in the expression of ER have been found in colorectal cancer specimens. These data strongly suggest the protective roles of E2 and ER against colorectal cancer. However, the mechanisms remain unexplored. LoVo cells were transient transfected to overexpress ER-beta, DNA fragmentation and caspase activity assay were performed to evaluate apoptotic effects. Western blotting was used to evaluate protein levels, and luciferase activity assay to measure the TNF-alpha promoter activity. Our data clearly demonstrated that E2 and ER-beta alone could upregulate p21 and p27 proteins, which further activate caspase-8 and caspase-9 to induce apoptosis in LoVo cell, and the ER-beta. effects were enhanced by E2. However, overexpressed ER-beta did not influence the expression and promoter activity of TNF-alpha. In addition, E2 and overexpressed ER-beta downregulated the beta-catenin proteins which cause the downregulation of its target genes, cyclin D1 and Rb, to inhibit the cell cycle and cell proliferation. The results indicate that overexpressed ER-beta may induce LoVo cell apoptosis and anti-proliferation by increasing p53 signaling in a ligand-dependent manner, and without hTNF-alpha involvement. Efforts aiming at enhancing ER-beta expression and/or activity may prove to be an attractive alternative therapy against colorectal cancer.
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PMID:Apoptotic effects of over-expressed estrogen receptor-beta on LoVo colon cancer cell is mediated by p53 signalings in a ligand-dependent manner. 1683 Jul 93


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