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

The cochaperone p23 is required for the chaperoning cycle of hsp90 and to enhance the maturation of several client proteins. Tosylcyclonovobiocic acids (4TCNA and 7TCNA) are potent analogs of novobiocin and induce cell cycle arrest, apoptosis and degradation of hsp90 client proteins in a panel of cancer cells. In this study, Western blotting shows that 4TCNA and 7TCNA triggered processing of the hsp90 cochaperone p23 in a dose-dependent manner. Small interfering RNA (siRNA)-mediated reduction of p23 expression in MCF-7 breast cancer cells did not block 4TCNA-induced caspase activation as assessed by the cleavage of PARP. This result indicates that 4TCNA-mediated cell death is a p23-independent process. In HT29 colon cancer cells, 4TCNA and 7TCNA up-regulated GRP78 and GRP94 supporting involvement of ER stress in apoptosis.
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PMID:Tosylcyclonovobiocic acids promote cleavage of the hsp90-associated cochaperone p23. 1911 25

Astragalus membranaceus has been used to ameliorate the side effects of anti-neoplastic drugs. We recently reported that total Astragalus saponins (AST) possess anti-tumor properties in human colon cancer cells and tumor xenografts. Nevertheless, the precise mechanism of action has not been fully elucidated. The present study aimed to unveil the anti-carcinogenic potential of AST in HepG2 human hepatocellular carcinoma (HCC) cells and to clarify the signaling pathway. We demonstrated here that AST downregulated expression of the HCC tumor marker alpha-fetoprotein and suppressed HepG2 cell growth by inducing apoptosis. AST also caused caspase activation, poly(ADP-ribose) polymerase (PARP) cleavage, nuclear chromatin condensation, with downregulation of the anti-apoptotic proteins bcl-2 and bcl-xL and decreased nuclear factor-kappa B (NF-kappaB)/DNA-binding activity. Concomitantly, expression of the phosphorylated form of the extracellular signal-regulated protein kinase (ERK) was prominently increased. Nevertheless, pretreatment of ERK inhibitor PD98059 did not attenuate AST-induced PARP cleavage. Taken together, these results exemplify that AST induced growth inhibition and promoted apoptosis in HepG2 cells through modulation of an ERK-independent NF-kappaB signaling pathway.
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PMID:Astragalus saponins induce apoptosis via an ERK-independent NF-kappaB signaling pathway in the human hepatocellular HepG2 cell line. 1914 42

We observed that treatment of prostate cancer cells for 24 h with magnolol, a phenolic component extracted from the root and stem bark of the oriental herb Magnolia officinalis, induced apoptotic cell death in a dose- and time-dependent manner. A sustained inhibition of the major survival signal, Akt, occurred in magnolol-treated cells. Treatment of PC-3 cells with an apoptosis-inducing concentration of magnolol (60 microM) resulted in a rapid decrease in the level of phosphorylated Akt leading to inhibition of its kinase activity. Magnolol treatment (60 microM) also caused a decrease in Ser((136)) phosphorylation of Bad (a proapoptotic protein), which is a downstream target of Akt. Protein interaction assay revealed that Bcl-xL, an anti-apoptotic protein, was associated with Bad during treatment with magnolol. We also observed that during treatment with magnolol, translocation of Bax to the mitochondrial membrane occurred and the translocation was accompanied by cytochrome c release, and cleavage of procaspase-8, -9, -3, and poly(ADP-ribose) polymerase (PARP). Similar results were observed in human colon cancer HCT116Bax(+/-) cell line, but not HCT116Bax(-/-) cell line. Interestingly, at similar concentrations (60 microM), magnolol treatment did not affect the viability of normal human prostate epithelial cell (PrEC) line. We also observed that apoptotic cell death by magnolol was associated with significant inhibition of pEGFR, pPI3K, and pAkt. These results suggest that one of the mechanisms of the apoptotic activity of magnolol involves its effect on epidermal growth factor receptor (EGFR)-mediated signaling transduction pathways.
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PMID:Magnolol induces apoptosis via inhibiting the EGFR/PI3K/Akt signaling pathway in human prostate cancer cells. 1922 60

Epidemiological evidence suggests that the intake of prebiotic dietary fibres, for example, inulin, protects against colorectal cancer. However, little is known about cellular responses to complex fermentation samples. Therefore, we prepared a fermentation supernatant fraction of inulin and studied biological properties in human colon cell lines, LT97 and HT29 (representing early and late stages of colon cancer). Inulin enriched with oligofructose (Synergy 1) was incubated under anaerobic conditions with faecal inocula and the supernatant fraction was characterised for content of SCFA and secondary bile acid deoxycholic acid (DCA). A Synergy fermentation supernatant fraction (SFS) and a synthetic fermentation mixture (SFM) mimicking the SFS in SCFA and DCA content were used in the concentration range of 1.25-20 % (v/v) for 24-72 h. The effects on cell growth were determined by quantifying DNA. Effects on apoptosis were analysed by measuring poly(ADP-ribose) polymerase (PARP) cleavage using Western blotting. Compared with the faecal blank, produced without the addition of inulin, the SFS resulted in an almost 2.5-fold increase of SCFA and 3.4-fold decrease of DCA. In comparison with HT29 cells, LT97 cells responded more sensitively to the growth-inhibitory activities. Additionally, a significant increase in PARP cleavage was observed in LT97 cells after incubation with the SFS, demonstrating induction of apoptosis. The present results indicate growth-inhibiting and apoptosis-inducing effects of fermentation supernatant fractions of inulin. Moreover, since early adenoma cells were found to be more sensitive, this may have important implications for chemoprevention when translated to the in vivo situation, because survival of early transformed cells could be reduced.
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PMID:Fermentation products of inulin-type fructans reduce proliferation and induce apoptosis in human colon tumour cells of different stages of carcinogenesis. 1925 May 71

Fisetin, or 3,3',4',7-tetrahydroxyflavone, is present in fruits and vegetables and has been previously reported to inhibit the proliferation of a variety of cancer cells (Lu X, Jung J, Cho HJ, Lim do Y, Lee HS, Chun HS, Kwon DY, Park JH. J Nutr 135: 2884-2890, 2005). We have demonstrated in a previous work that 20-60 micromol/l fisetin inhibits cyclin-dependent kinase activities resulting in cell cycle arrest in HT-29 colon cancer cells. In the present study, we attempted to characterize the mechanisms by which fisetin induces apoptosis in HCT-116 cells. DNA condensations, cleavage of poly(ADP-ribose) polymerase (PARP), and cleavage of caspases 9, 7, and 3 were induced in HCT-116 cells treated with 5-20 micromol/l of fisetin. Fisetin induced a reduction in the protein levels of antiapoptotic Bcl-xL and Bcl-2 and an increase in the levels of proapoptotic Bak and Bim. Fisetin did not affect the Bax protein levels, but induced the mitochondrial translocation of this protein. Fisetin also enhanced the permeability of the mitochondrial membrane and induced the release of cytochrome c and Smac/Diablo. Additionally, fisetin caused an increase in the protein levels of cleaved caspase-8, Fas ligand, death receptor 5, and TNF-related apoptosis-inducing ligand, and the caspase-8 inhibitor Z-IETD-FMK suppressed fisetin-induced apoptosis and the activation of caspase-3. Furthermore, fisetin increases p53 protein levels, and the inhibition of p53 expression by small interference RNA resulted in a decrease in the fisetin-induced translocation of Bax to the mitochondria, release of mono- and oligonucleosome in the cytoplasm, and PARP cleavage. These results show that fisetin induces apoptosis in HCT-116 cells via the activation of the death receptor- and mitochondrial-dependent pathway and subsequent activation of the caspase cascade. The induction of p53 results in the translocation of Bax to the mitochondria, which contributes to fisetin-induced apoptosis in HCT-116 cells.
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PMID:Induction of p53 contributes to apoptosis of HCT-116 human colon cancer cells induced by the dietary compound fisetin. 1926 55

Macroautophagy is a process by which cytoplasmic content and organelles are sequestered by double-membrane bound vesicles and subsequently delivered to lysosomes for degradation. Macroautophagy serves as a major intracellular pathway for protein degradation and as a pro-survival mechanism in time of stress by generating nutrients. In the present study, bafilomycin A(1), a vacuolar type H(+)-ATPase inhibitor, suppresses macroautophagy by preventing acidification of lysosomes in colon cancer cells. Diminished macroautophagy was evidenced by the accumulation of undegraded LC3 protein. Suppression of macroautophagy by bafilomycin A(1) induced G(0)/G(1) cell cycle arrest and apoptosis which were accompanied by the down-regulation of cyclin D(1) and cyclin E, the up-regulation of p21(Cip1) as well as cleavages of caspases-3, -7, -8, and -9 and PARP. Further investigation revealed that bafilomycin A(1) increased the phosphorylation of ERK, JNK, and p38. In this regard, p38 inhibitor partially reversed the anti-proliferative effect of bafilomycin A(1). To conclude, inhibition of macroautophagy by bafilomycin A(1) lowers G(1)-S transition and induces apoptosis in colon cancer cells. Our results not only indicate that inhibitors of macroautophagy may be used therapeutically to inhibit cancer growth, but also delineate the relationship between macroautophagy and apoptosis.
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PMID:Inhibition of macroautophagy by bafilomycin A1 lowers proliferation and induces apoptosis in colon cancer cells. 1928 6

The apoptotic effects of docosahexaenoic acid (DHA) and other omega-3 polyunsaturated fatty acids (PUFAs) have been documented in cell and animal studies. The molecular mechanism by which DHA induces apoptosis is unclear. Although there is no direct evidence, some studies have suggested that DNA damage generated through lipid peroxidation may be involved. Our previous studies showed that DHA, because it has a high degree of unsaturation, can give rise to the acrolein-derived 1,N(2)-propanodeoxyguanosine (Acr-dG) as a major class of DNA adducts via lipid oxidation. As a first step to investigate the possible role of oxidative DNA damage in apoptosis induced by DHA, we examined the relationships between oxidative DNA damage and apoptosis caused by DHA in human colon cancer HT-29 cells. Apoptosis and oxidative DNA damage, including Acr-dG and 8-oxo-deoxyguanosine (8-oxo-dG) formation, in cells treated with DHA and omega-6 PUFAs, including arachidonic acid (AA) and linoleic acid (LA), were measured. DHA induced apoptosis in a dose- and time-dependent manner with a concentration range from 0 to 300 microM as indicated by increased caspase-3 activity and PARP cleavage. In contrast, AA and LA had little or no effect at these concentrations. The Acr-dG levels were increased in HT-29 cells treated with DHA at 240 and 300 microM, and the increases were correlated with the induction of apoptosis at these concentrations, while no significant changes were observed for 8-oxo-dG. Because proteins may compete with DNA to react with acrolein, we then examined the effects of BSA on DHA-induced apoptosis and oxidative DNA damage. The addition of BSA to HT-29 cell culture media significantly decreases Acr-dG levels with a concomitant decrease in the apoptosis induced by DHA. The reduced Acr-dG formation is attributed to the reaction of BSA with acrolein as indicated by increased levels of total protein carbonyls. Similar correlations between Acr-dG formation and apoptosis were observed in HT-29 cells directly incubated with 0-200 microM acrolein. Additionally, DHA treatment increased the level of DNA strand breaks and caused cell cycle arrested at G1 phase. Taken together, these results demonstrate the parallel relationships between Acr-dG level and apoptosis in HT-29 cells, suggesting that the formation of Acr-dG in cellular DNA may contribute to apoptosis induced by DHA.
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PMID:Acrolein-derived DNA adduct formation in human colon cancer cells: its role in apoptosis induction by docosahexaenoic acid. 1934 Dec 37

Astragalus membranaceus has been used to ameliorate the side effects of antineoplastic drugs because of its immunomodulating nature. We had recently demonstrated that total Astragalus saponins (AST) possess anticarcinogenic and proapoptotic properties in human colon cancer cells and tumor xenograft. In this study, we identified NSAID-activated gene (NAG-1) as a potential molecular target of AST. The growth-inhibitory and proapoptotic effects of AST were assessed in a panel of human cancer cell lines. Hoechst 33342 nuclear staining, Annexin V-FITC/propidium iodide staining, Western immunoblotting, real-time PCR, luciferase reporter assay and electrophoretic mobility shift assay were conducted to determine the association of NAG-1 and related transcription factors with AST during its regulation of apoptotic activities. Moreover, the combined proapoptotic and NAG-1 promoting activities of AST and/or inhibitors of the PI3K-Akt pathway were also examined. AST caused overexpression of NAG-1, leading to PARP cleavage and apoptosis. The induction of NAG-1 promoter activity by the drug was associated with increased gene expression, in addition to prior increase in Egr-1 expression and DNA binding activity. AST-induced NAG-1 activation was intensified when PI3K inhibitor LY294002 or Akt inhibitor was co-treated and reversed by NAG-1 siRNA transfection. Nevertheless, the extent of NAG-1 induction could not be altered by the ERK inhibitor PD98059. Our results indicate that NAG-1 is a potential molecular target of AST in its antitumorigenic and proapoptotic actions, which would have additive effects when used along with PI3K-Akt inhibitors. The information obtained could facilitate future development of a novel target-specific chemotherapeutic agent with known molecular pathway.
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PMID:A novel anticancer effect of Astragalus saponins: Transcriptional activation of NSAID-activated gene. 1938 47

Acetyl-CoA carboxylase-alpha (ACCA) is a rate-limiting enzyme in long chain fatty acid synthesis, playing a critical role in cellular energy storage and lipid synthesis. ACCA is upregulated in multiple types of human cancers and small interfering RNA-mediated ACCA silencing in human breast and prostate cancer cells results in oxidative stress and apoptosis. This study reports for the first time that TOFA (5-tetradecyloxy-2-furoic acid), an allosteric inhibitor of ACCA, is cytotoxic to lung cancer cells NCI-H460 and colon carcinoma cells HCT-8 and HCT-15, with an IC(50) at approximately 5.0, 5.0, and 4.5 microg/ml, respectively. TOFA at 1.0-20.0 microg/ml effectively blocked fatty acid synthesis and induced cell death in a dose-dependent manner. The cell death was characterized with PARP cleavage, DNA fragmentation, and annexin-V staining, all of which are the features of the apoptosis. Supplementing simultaneously the cells with palmitic acids (100 microM), the end-products of the fatty acid synthesis pathway, prevented the apoptosis induced by TOFA. Taken together, these data suggest that TOFA is a potent cytotoxic agent to lung and colon cancer cells, inducing apoptosis through disturbing their fatty acid synthesis.
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PMID:Acetyl-CoA carboxylase-alpha inhibitor TOFA induces human cancer cell apoptosis. 1945 May 51

The insulin-like growth factor (IGF) system plays a critical role in normal growth and development as well as in malignant states. Most of the biological activities of the IGFs are mediated by the IGF-IR, which is over-expressed in most tumours and cancer cell lines. Fatty acids have critical roles in both systemic physiological processes (e.g. metabolism) and cellular events (e.g. proliferation, apoptosis, signal transduction, and gene expression). Alpha-linolenic acid (ALA) and linoleic acid (LA) are essential fatty acids of the omega-3 and omega-6 families, respectively. The aim of this study was to investigate the potential interactions between fatty acids and the IGF signal transduction pathways, and to evaluate the impact of this interplay on colon cancer cells survival and proliferation. Results of Western blot analyses revealed that ALA and LA enhanced the ligand-induced IGF-IR phosphorylation and, in addition, increased receptor phosphorylation in an IGF-I independent manner. Furthermore, fatty acid treatment led to phosphorylation of downstream signalling molecules, including Akt and Erk. In addition, FACS analysis and apoptosis measurements indicated that ALA and LA have a potential mitogenic effect on HCT116 cells, as reflected by the number of cells in S phase and by a reduction of PARP cleavage, implying a reduction in apoptotic activity. In summary, our results provide evidence that omega-3 and omega-6 fatty acids modulate IGF-I action in colon cancer cells.
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PMID:Effects of omega-3 and omega-6 fatty acids on IGF-I receptor signalling in colorectal cancer cells. 1948 May 65


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