Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Death receptors of the Tumor Necrosis Factor (TNF) family form membrane-bound self-activating signaling complexes that initiate apoptosis through cleavage of proximal caspases including CASP8 and 10. Here we show that overexpression of the cytoplasmic domain (CD) of the DR4 TRAIL receptor (TNFRSF10A, TRAIL R1) in human breast, lung, and colon cancer cell lines, using an adenovirus vector (Ad-DR4-CD), leads to p53-independent apoptotic cell death involving cleavage of CASP8 and 10 proximally and CASP3, 6, and 7 distally. DR4-CD overexpression also leads to cleavage of poly(ADP-ribose) polymerase (PARP) and the DNA fragmentation factor (DFF45; ICAD). Importantly, normal lung fibroblasts are resistant to DR4-CD overexpression and show no evidence of PARP-, CASP8- or CASP3-cleavage despite similar levels of adenovirus-delivered DR4-CD protein as the cancer cells. These results suggest that DR4 may signal death through known caspases and that further studies are required to evaluate Ad-DR4-CD as a novel anti-cancer agent. Finally, we show that overexpression of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) (CDKN1A), or its N-terminal 91 amino acids containing cell cycle-inhibitory activity, inhibits DR4-CD-dependent proximal caspase cleavage. The blockage of initiator caspase activation provides a novel insight into how p21 may suppress apoptosis and enhance cell survival.
 ...
PMID:p21(WAF1/CIP1) inhibits initiator caspase cleavage by TRAIL death receptor DR4. 1069 97

The peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-activated transcription factor belonging to the steroid receptor superfamily. It is a key regulator of adipogenic differentiation, the ligands of which have also been demonstrated to induce differentiation in human breast and colon cancer cell lines. This study examined PPARgamma, in non-small cell lung cancer (NSCLC). PPARgamma mRNA and protein were expressed in NSCLC cell lines, with highest levels in adenocarcinomas. PPARgamma protein was also expressed in 50% of primary lung cancers by immunohistochemistry. Treatment of multiple cell lines with two distinct PPARgamma ligands in the presence of serum resulted in growth arrest, irreversible loss of capacity for anchorage-independent growth, decreased activity and expression of matrix metalloproteinase 2, and modulation of multiple markers in a manner consistent with differentiation. Specifically, there was up-regulation of general markers of the differentiated state such as gelsolin, Mad, and p21. Down-regulation of specific markers of progenitor lineages for the peripheral lung, i.e., the type II pneumocyte lineage markers MUC1 and surfactant protein-A and the Clara cell lineage marker CC10, also occurred. In addition, HTI56, a marker of terminally differentiated type I pneumocytes, was also induced. Consistent with a more mature, less malignant phenotype, ligand treatment also inhibited the expression of cyclin D1 and led to hypophosphorylation of the retinoblastoma protein. In contrast, in the absence of serum, ligand treatment rapidly resulted in apoptosis and substantially earlier onset of differentiation. Taken together, these results show that depending on the growth milieu, ligands of PPARgamma induce differentiation and apoptosis in NSCLC, suggesting clinical utility for these agents.
 ...
PMID:Induction of differentiation and apoptosis by ligands of peroxisome proliferator-activated receptor gamma in non-small cell lung cancer. 1070 35

The aim of the present study was to assess the cytotoxicity of manumycin, a specific inhibitor of farnesyl:protein transferase, as well as its effects on protein isoprenylation and kinase-dependent signal transduction in COLO320-DM human colon adenocarcinoma which harbours a wild-type K-ras gene. Immunoblot analysis of isolated cell membranes and total cellular lysates of COLO320-DM cells demonstrated that manumycin dose-dependently reduced p21 ras farnesylation with a 50% inhibitory concentration (IC50) of 2.51 +/- 0.11 microM and 2.68 +/- 0.20 microM, respectively, while the geranylgeranylation of p21 rhoA and p21rap1 was not affected. Manumycin dose-dependently inhibited (IC50 = 2.40 +/- 0.67 microM) the phosphorylation of the mitogen-activated protein kinase/extracellular-regulated kinase 2 (p42MAPK/ERK2), the main cytoplasmic effector of p21ras, as well as COLO320-DM cell growth (IC50 = 3.58 +/- 0.27 microM) without affecting the biosynthesis of cholesterol. Mevalonic acid (MVA, 100 microM), a substrate of the isoprenoid synthesis, was unable to protect COLO320-DM cells from manumycin cytotoxicity. Finally, manumycin 1-25 microM for 24-72 h induced oligonucleosomal fragmentation in a dose- and time-dependent manner and MVA did not protect COLO320-DM cells from undergoing DNA cleavage. The present findings indicate that the inhibition of p21ras processing and signal transduction by manumycin is associated with marked inhibition of cell proliferation and apoptosis in colon cancer cells and the effect on cell growth does not require the presence of a mutated ras gene for maximal expression of chemotherapeutic activity.
 ...
PMID:Manumycin inhibits ras signal transduction pathway and induces apoptosis in COLO320-DM human colon tumour cells. 1073 65

Tumour growth is regulated by a balance between proliferation, growth arrest and programmed cell death (apoptosis). Until recently, the majority of the studies dealing with oncogenesis has been focused on the regulation of cell proliferation. There is now growing understanding that control of growth arrest and apoptosis play key roles in the development of human cancer and in cancer treatment. Some of the more heavily studied proteins of importance for the control of growth arrest and apoptosis are p53, p21, bcl-2 and bax. Alterations in the p53 protein may lead to malignant transformation and defect therapy response, most likely as a result of defective p53-dependent apoptosis. In addition, p21 (WAF1/CIP1) is involved in cell-cycle arrest and probably in induction of p53-dependent apoptosis. Proteins belonging to the bcl-2 family are also important for normal apoptosis. Overexpression of bcl-2 protein is thought to reduce the apoptotic capacity, while bax protein seems to be necessary for induction of apoptosis. In this study, we have immunostained tissues from 93 primary colon carcinomas and have examined the expression of p53, p21 (WAF1/CIP1), bcl-2 bax, pRb and cyclin D1 for evaluation of their roles in colon-cancer progression. A highly significant association between p53 accumulation and downregulation of p21 (WAF1/CIP1) was seen. We also found a strong association between reduced/absent p21 and the development of metastases and death due to cancer disease. Cyclin D1, bcl-2 and bax protein failed to have independent prognostic impacts. Bcl-2 and bax protein levels showed an inverse relationship. The results of the present study indicate that reduced p21 protein levels play an important role in progression of colon cancer. We concluded that evaluation of p21 expression in primary colon carcinomas at the time of surgery might be a valuable tool in defining patients with a high risk of developing metastases.
 ...
PMID:Protein expression of p53, p21 (WAF1/CIP1), bcl-2, Bax, cyclin D1 and pRb in human colon carcinomas. 1078 80

Photodynamic therapy (PDT) using the silicon phthalocyanine photosensitizer Pc 4 [HOSiPcOSi(CH3)2(CH2)3N-(CH3)2] is an oxidative stress associated with induction of apoptosis in various cell types. We assessed the effectiveness of Pc 4-PDT on SW480 colon cancer xenografts grown in athymic nude mice. Animals bearing xenografts were treated with 1 mg/kg body weight Pc 4 and 48 h later were irradiated with 150 J/cm2 672-nm light from a diode laser delivered at 150 mW/cm2. Biochemical studies were performed in xenografts resected at various time points up to 26 h after Pc 4-PDT treatment, whereas tumor size was evaluated over a 4-week period in parallel experiments. In the tumors resected for biochemical studies, apoptosis was visualized by activation of caspase-9 and caspase-3 and a gradual increase in the cleavage of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) to a maximum of approximately 60% of the total PARP present at approximately 26 h. At that time all Pc 4-PDT-treated tumors had regressed significantly. Two signaling responses that have previously been shown to be associated with Pc 4-PDT-induced apoptosis in cultured cells, p38 mitogen-activated protein kinase and p21/WAF1/Cip1, were examined. A marked increase in phosphorylation of p38 was observed within 1 h after Pc 4-PDT without changes in levels of the p38 protein. Levels of p21 were not altered in the xenografts in correspondence with the presence of mutant p53 in SW480 cells. Evaluation of tumor size showed that tumor growth resumed after a delay of 9-15 days. Our results suggest that: (a) Pc 4-PDT is effective in the treatment of SW480 human colon cancer xenografts independent of p53 status; (b) PARP cleavage may be mediated by caspase-9 and caspase-3 activation in the Pc 4-PDT-treated tumors; and (c) p38 phosphorylation may be a trigger of apoptosis in response to PDT in vivo in this tumor model.
 ...
PMID:Photodynamic therapy with the phthalocyanine photosensitizer Pc 4 of SW480 human colon cancer xenografts in athymic mice. 1081 28

Transforming growth factor-beta1 (TGF-beta1) can act as a tumor suppressor or a tumor promoter depending on the characteristics of the malignant cell. Each of three Ki-ras(G12V) transfectants of HD6-4 colon cancer cells had been shown to be more aggressive in vivo than controls in earlier studies (Yan, Z., Chen, M., Perucho, M., and Friedman, E. (1997) J. Biol. Chem. 272, 30928-30936). We now show that stable expression of oncogenic Ki-ras(G12V) converts the HD6-4 colon cancer cell line from insensitive to TGF-beta1 to growth-promoted by TGF-beta1. Each of three Ki-ras(G12V) transfectants responded to TGF-beta1 by an increase in proliferation and by decreasing the abundance of the Cdk inhibitor p21 and the tumor suppressor PTEN, whereas each of three wild-type Ki-ras transfectants remained unresponsive to TGF-beta1. The wild-type Ki-ras transfectants lack functional TGF-beta receptors, whereas all three Ki-ras(G12V) transfectants expressed functional TGF-beta receptors that bound (125)I-TGF-beta1. The previous studies showed that in cells with wild-type Ki-ras, TGF-beta receptors were not mutated, and receptor proteins were transported to the cell surface, but post-translational modification of TGF-beta receptor III (TbetaRIII) was incomplete. We now show that the betaglycan form of TbetaRIII is highly modified following translation when transiently expressed in Ki-ras(G12V) cells, whereas no such post-translational modification of TbetaRIII occurs in control cells. Antisense oligonucleotides directed to Ki-Ras decreased both TbetaRIII post-translational modification in Ki-ras(G12V) cells and TGF-beta1 down-regulation of p21, demonstrating the direct effect of mutant Ras. Therefore, one mechanism by which mutant Ki-Ras confers a more aggressive tumor phenotype is by enhancing TbetaRIII post-translational modification.
 ...
PMID:Oncogenic Ki-ras confers a more aggressive colon cancer phenotype through modification of transforming growth factor-beta receptor III. 1102 59

Butyrate is a short chain fatty acid (SCFA) produced by bacterial fermentation of dietary fibers in the colon lumen which severely affects the proliferation of colon cancer cells in in vitro experiments. Although butyrate is able to interfere with numerous cellular targets including cell cycle regulator expression, little is known about butyrate metabolism and its possible involvement in its effect upon colon carcinoma cell growth. In this study, we found that HT-29 Glc-/+ cells strongly accumulated and oxidized sodium butyrate without producing ketone bodies, nor modifying oxygen consumption nor mitochondrial ATP synthesis. HT-29 cells accumulated and oxidized sodium acetate at a higher level than butyrate. However, sodium butyrate, but not sodium acetate, reduced cell growth and increased the expression of the cell cycle effector cyclin D3 and the inhibitor of the G1/S cdk-cyclin complexes p21/WAF1/Cip1, demonstrating that butyrate metabolism downstream of acetyl-CoA synthesis is not required for the growth-restraining effect of this SCFA. Furthermore, HT-29 cells modestly incorporated the 14C-labelled carbon from sodium butyrate into cellular triacylglycerols and phospholipids. This incorporation was greatly increased when D-glucose was present in the incubation medium, corresponding to the capacity of hexose to circulate in the pentose phosphate pathway allowing NADPH synthesis required for lipogenesis. Interestingly, when HT-29 cells were cultured in the presence of sodium butyrate, their capacity to incorporate 14C-labelled sodium butyrate into triacylglycerols and phospholipids was increased more than twofold. In such experimental conditions, HT-29 cells when observed under an electronic microscope, were found to be characterized by an accumulation of lipid droplets in the cytosol. Our data strongly suggest that butyrate acts upon colon carcinoma cells upstream of acetyl-CoA synthesis. In contrast, the metabolism downstream of acetyl-CoA [i.e. oxidation in the tricarboxylic acid (TCA) cycle and lipid synthesis] likely acts as a regulator of butyrate intracellular concentration.
 ...
PMID:Butyrate metabolism upstream and downstream acetyl-CoA synthesis and growth control of human colon carcinoma cells. 1102 87

The ATP-binding cassette transmembrane proteins play an important role in transport of drugs as well as of biologically active endogenous substances. The human multidrug resistance-associated protein (MRP) subfamily consists of at least six members, exhibiting a wide spectrum of biological functions. MRP1 operates as an ATP-dependent primary active transporter for substrates conjugated with glucuronide, sulfate or glutathione. Leukotriene C4 is an important endogenous substrate for MRP1. Glutathione serves as a cofactor in MRP1-mediated drug transport as well. Genes encoding both MRP1 and the catalytic subunit of gamma-glutamylcysteine synthetase (gamma-GCS) are coordinately regulated in cultured cancer cell lines as well as colorectal cancer tissues from colon cancer patients. The induction of MRP1 and gamma-GCS expression by oxidative stress varies among different cell lines, and p53 mutations are associated with elevated levels of induction. To modulate the transport function of MRP1, we have synthesized novel glutathione derivatives as photoreactive biochemical probes targeting the transporter protein. GIF-0019 restored the cellular sensitivity of MRP1-overexpressing drug-resistant cancer cells to anticancer prostaglandins in vitro, which was characterized by enhanced mRNA levels of the cyclin-dependent kinase inhibitor p21, suppressed c-myc expression and G1 arrest.
 ...
PMID:The human multidrug resistance-associated protein (MRP) gene family: from biological function to drug molecular design. 1109 46

The p21(WAF1)induces cell cycle arrest at G(1)and its expression is regulated by the functional p53. TNF-alpha induced expression of p21(WAF1)at protein and mRNA levels in a dose-dependent fashion with an association with G(1)-arrest in human colon cancer cells WiDr that carry mutated p53 at codon 273 (His(273)). However, TNF-alpha did not affect the levels of the Bax protein, which also has p53-binding sites on its promoter and causes apoptosis. Further experiments suggested that cycloheximide (CHX), a protein synthesis inhibitor, increased the levels of p21(WAF1)mRNA and the induction of p21(WAF1)mRNA by TNF-alpha did not require new protein synthesis. Co-transfection of the p53 His(273)expression construct with a luciferase gene controlled by the p21(WAF1)promoter showed that the p53 His(273)was inactive, although TNF-alpha increased the transcriptional rate of p21(WAF1)in these cells. Further study found that TNF-alpha markedly stabilized the p21(WAF1)protein. These findings suggest that TNF-alpha induces expression of p21(WAF1)through a distinct pathway from Bax and that protein stabilization is an important mechanism in the expression of p21(WAF1)independent of p53.
 ...
PMID:TNF-alpha induced p21(WAF1) but not Bax in colon cancer cells WiDr with mutated p53: important role of protein stabilization. 1109 43

Antitumor prostaglandins(PGs) such as Delta12-PGJ2 and Delta7-PGA1 possess a cyclopentenone or cross-conjugated dienone structures. Antitumor PGs are actively incorporated through cell membrane and control gene expression. Very recent studies clarified that P53 independent expression of p21 and gadd 45, activation of PPARgamma are involved in antitumor mechanism of these PGs. At the low concentration, these PGs exhibit physiological or pathological activity such as osteoblast calcification, promotion of colon cancer cell proliferation. COMPARE PROGRAM using human 38 tumor cell lines suggested that antitumor mechanism of Delta7-PGA1 and 13, 14-dihydro-15-deoxy-Delta7-PGA1 methyl ester (TEI-9826) are quite different from other anticancer agents which are clinically used. Lipid microspheres and Lipiodol formulation were examined as dosage form of the PGs and lipid microspheres were selected for further study. At first lipid microspheres integrated TEI-9038 (Lipo TEI-9038) was chosen as a candidate for clinical trial. However Lipo TEI-9038 failed to exhibit substantial antitumor effect because of its enzymatic instability and toxicity in vivo. Lipo TEI-9826 was then selected as promising candidate for clinical trial because of its stability in serum. Lipo TEI-9826 exhibited marked antitumor effect in several animal models including CDDP resistant nude mice model. Pharmacokinetic and toxicological studies using rats suggested that continuous infusion is the most suitable administration method for Lipo TEI-9826. New type emulsifier, Controlled High Pressure Process Homogenizer (De-BEE 2000 and mini De-BEE) was developed during the preclinical studies on manufacturing process of Lipo TEI-9826. These results warrant the clinical trial for Lipo TEI-9826 in CDDP resistant cancer.
 ...
PMID:Preparation and evaluation of o/w type emulsions containing antitumor prostaglandin. 1110 98


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