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)

Laboratory and epidemiological studies suggest that butyrate, a metabolic product of microbial fermentation of dietary fibre, and aspirin, a non-steroidal antiphlogistic drug, both reduce the risk of developing colon cancer. Notably, few data exist on potential interactions of these two substances. In this study, the effects of a butyrate-aspirin combination on human colon cancer cells were compared with treatment with aspirin or butyrate alone. Both substances decreased proliferation and induced differentiation and apoptosis. Butyrate reduced mutant p53 expression, whereas aspirin did not affect p53 expression. Butyrate-induced apoptosis correlated with an increase in Bak expression and a decrease in the expression of Bcl-XL. Aspirin had no effect on the investigated apoptosis-controlling factors. The antiproliferative and pro-apoptotic effects of the butyrate-aspirin combination were markedly enhanced. The combination resulted in a stronger decrease in the expression of PCNA and cdk2. Our data suggest that the anticarcinogenic effect of aspirin might effectively be augmented by combination with the short-chain fatty acid butyrate.
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PMID:Butyrate and aspirin in combination have an enhanced effect on apoptosis in human colorectal cancer cells. 1213 61

To evaluate resistance that develops in cancer cells during treatment with adenoviral vectors expressing proapoptotic genes, we repeatedly treated the human colon cancer cell line DLD1 with adenoviral vectors expressing the human Bax gene and the human tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene. DLD1 cells resistant to the Bax- or TRAIL-expressing adenoviral vectors were then selected and designated as DLD1/Bax-R or DLD1/TRAIL-R cells, respectively. Further study showed that resistance in DLD1/Bax-R cells was caused by resistance to adenoviral infection, which can be overcome by dose escalation of the adenoviral vectors. However, resistance in DLD1/TRAIL-R cells was caused by resistance to the TRAIL gene. Therefore, different mechanisms are involved in the development of resistance during adenovirus-mediated proapoptotic gene therapy. A survey of molecules involved in TRAIL- or Bax-mediated apoptotic pathways showed no significant change in expression of death receptors, death decoy receptors; FLIP; Bcl-2; Bcl-xS; Bax; Bak; XIAP or caspase-2, -7, -8, or -9 in either DLD1/Bax-R or DLD1/TRAIL-R cells. Bcl-xL expression detected in both mRNA and protein level assays was three times higher in DLD1/TRAIL-R cells than in parental or DLD1/Bax-R cells. However, transfection of DLD1 cells with the Bcl-xL gene showed that overexpression of Bcl-xL is not sufficient for the resistance. Moreover, DLD1/Bax-R cells were sensitive to adenoviral vectors that expressed the TRAIL gene, but resistant to adenoviral vectors that expressed the Bak gene. In contrast, DLD1/TRAIL-R cells were sensitive to adenoviral vectors that expressed either Bax or Bak gene. Thus, alternative application of adenoviral vectors that expressed proapoptotic genes in different pathways or different cell killing models may delay or prevent development of resistance in adenovirus-mediated proapoptotic gene therapy.
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PMID:Mechanisms involved in development of resistance to adenovirus-mediated proapoptotic gene therapy in DLD1 human colon cancer cell line. 1221 94

Chlorophyllin (CHL), an antimutagenic and anticarcinogenic water-soluble derivative of chlorophyll, was recently found to be highly effective as a chemopreventive agent in a high-risk population exposed unavoidably to aflatoxin B(1) in the diet (P. A. Egner et al., Proc. Natl. Acad. Sci. USA, 98: 14601-14606, 2001). The current study examined the response of HCT116 human colon cancer cells to CHL treatment. Cells exposed to concentrations in the range 0.0625-0.5 mM CHL underwent growth arrest and apoptosis after 24 h, with the formation of a sub-G(1) peak in the attached cell population and nuclear condensation in the floating cell population. There was a concentration-dependent attenuation of mitochondrial membrane potential (deltapsi(m)) without the release of cytochrome c or activation of the caspase-9/caspase-3/poly(ADP-ribose) polymerase pathway. However, apoptosis-inducing factor was released from mitochondria into the cytosol and translocated to the nucleus, leading to concentration-dependent cleavage of nuclear lamins. The upstream mediators of this CHL-induced apoptosis pathway were identified as caspase-8/caspase-6 and truncated Bid, acting in conjunction with other proapoptotic members of the Bcl-2 family, such as Bak. These findings suggest that CHL might trigger apoptosis via interaction with putative "death receptors" in the plasma membrane of cancer cells, leading to initial cleavage of procaspase-8 and activation of subsequent downstream events, resulting in the destruction of nuclear lamins. Importantly, E-cadherin and alkaline phosphatase, which are indicators of cell differentiation, were strongly induced at all concentrations of CHL. Thus, in addition to being an effective blocking agent during the initiation phase, these findings support a role for CHL as a suppressing agent and as a possible novel therapeutic strategy directed toward aberrant cell proliferation in the colon.
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PMID:Caspase-8 and apoptosis-inducing factor mediate a cytochrome c-independent pathway of apoptosis in human colon cancer cells induced by the dietary phytochemical chlorophyllin. 1264 85

Resveratrol, a polyphenol found in grape skin and various other food products, may function as a cancer chemopreventive agent for colon and other malignant tumors and possesses a chemotherapeutic potential through its ability to trigger apoptosis in tumor cells. The present study analyses the molecular mechanisms of resveratrol-induced apoptosis in colon cancer cells, with special attention to the role of the death receptor Fas in this pathway. We show that, in the 10-100 microm range of concentrations, resveratrol activates various caspases and triggers apoptosis in SW480 human colon cancer cells. Caspase activation is associated with accumulation of the pro-apoptotic proteins Bax and Bak that undergo conformational changes and relocalization to the mitochondria. Resveratrol does not modulate the expression of Fas and Fas-ligand (FasL) at the surface of cancer cells, and inhibition of the Fas/FasL interaction does not influence the apoptotic response to the molecule. Resveratrol induces the clustering of Fas and its redistribution in cholesterol and sphingolipid-rich fractions of SW480 cells, together with FADD and procaspase-8. This redistribution is associated with the formation of a death-inducing signaling complex (DISC). Transient transfection of either a dominant-negative mutant of FADD, E8, or MC159 viral proteins that interfere with the DISC function, decreases the apoptotic response of SW480 cells to resveratrol and partially prevents resveratrol-induced Bax and Bak conformational changes. Altogether, these results indicate that the ability of resveratrol to induce the redistribution of Fas receptor in membrane rafts may contribute to the molecule's ability to trigger apoptosis in colon cancer cells.
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PMID:Resveratrol-induced apoptosis is associated with Fas redistribution in the rafts and the formation of a death-inducing signaling complex in colon cancer cells. 1290 49

We demonstrate that PS-341, a small molecule inhibitor of the proteasome, markedly sensitizes resistant prostate, colon, and bladder cancer cells to TNF-like apoptosis-inducing ligand (TRAIL)-induced apoptosis irrespective of Bcl-xL overexpression. PS-341 treatment by itself does not affect the levels of Bax, Bak, caspases 3 and 8, c-Flip or FADD, but elevates levels of TRAIL receptors DR4 and DR5. This increase in receptor protein levels is associated with the ubiquitination of the DR5 protein. When PS-341 is combined with TRAIL, the levels of activated caspase 8 and cleaved Bid are substantially increased. In Bax-negative TRAIL-resistant HC-4 colon cancer cells, the combination of PS-341 and TRAIL overcomes the block to activation of the mitochondrial pathway and causes SMAC and cytochrome c release followed by apoptosis. Similarly, murine embryonic fibroblasts lacking Bax undergo apoptosis when exposed to the combination of PS-341 and TRAIL; however, fibroblasts lacking Bak are significantly resistant. Taken together, these findings indicate that PS-341 enhances TRAIL-induced apoptosis by increasing the cleavage of caspase 8, causing Bak-dependent release of mitochondrial proapoptotic proteins.
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PMID:The proteasome inhibitor PS-341 overcomes TRAIL resistance in Bax and caspase 9-negative or Bcl-xL overexpressing cells. 1290 78

Anticancer drugs often show complex mechanisms of action, including effects on multiple cellular targets. Detailed understanding of these intricate effects is important for the understanding of cytotoxicity. In this study, we examined apoptosis induction by ellipticines, a class of cytotoxic plant alkaloids known to inhibit topoisomerase II. The potent ellipticine derivative 6-propanamine ellipticine (6-PA-ELL) induced rapid apoptosis in MDA-MB-231 breast cancer cells, preceded by a conformational change in Bak and cytochrome c release. Experiments using knock-out mouse embryo fibroblasts established that Bak was of particular importance for cytotoxicity. 6-PA-ELL increased the expression of the endoplasmic reticulum chaperones GRP78/BiP and GRP94, suggesting induction of endoplasmic reticulum stress. Induction of GRP78 expression was dependent on the endoplasmic reticulum stress response element (ERSE) of the GRP78 promoter. Examination of different ellipticine derivatives revealed a correlation between pro-apoptotic activity and the ability to induce GRP78 expression. Furthermore, 6-PA-ELL was found to induce splicing of the mRNA encoding the XBP1 transcription factor, characteristic of endoplasmic reticulum stress, and to induce activation of the endoplasmic reticulum-specific caspase-12 in mouse colon cancer cells. We finally demonstrate that 6-PA-ELL induces apoptotic signaling also in enucleated cells, consistent with the existence of a cytoplasmic target for this compound. Our data suggest that induction of endoplasmic reticulum stress may contribute to the cytotoxicity of ellipticines.
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PMID:Induction of endoplasmic reticulum stress by ellipticine plant alkaloids. 1507 93

LIGHT [homologous to lymphotoxins, shows inducible expression, and competes with herpes simplex virus glycoprotein D for herpes virus entry mediator (HVEM/TR2)] is a new member of TNF superfamily. The HT-29 colon cancer cell line is the most sensitive to LIGHT-induced, IFNg-mediated apoptosis among the cell lines we have examined so far. Besides downregulation of Bcl-XL, upregulation of Bak, and activation of both PARP [poly (ADP-ribose) polymerase] and DFF45 (DNA fragmentation factor), LIGHT-induced, IFNg-mediated apoptosis of HT-29 cells involves extensive caspase activation. Caspase-8 and caspase-9 activation, as shown by their cleavages appeared as early as 24 h after treatment, whereas caspase-3 and caspase-7 activation, as shown by their cleavages occurred after 72 h of LIGHT treatment. Caspase-3 inhibitor Z-DEVD-FMK (benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone) and a broad range caspase inhibitor Z-VAD-FMK (benzyloxycarbonyl-Val-Ala-Asp fluoromethylketone) were able to block LIGHT-induced, IFNg-mediated apoptosis of HT-29 cells. The activity of caspase-3, which is one of the major executioner caspases, was found to be inhibited by both Z-DEVD-MFK and Z-VAD-FMK. These results suggest that LIGHT-induced, IFNg-mediated apoptosis of HT-29 cells is caspase-dependent, and LIGHT signaling is mediated through both death receptor and mitochondria pathways.
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PMID:LIGHT sensitizes IFN-gamma-mediated apoptosis of HT-29 human carcinoma cells through both death receptor and mitochondria pathways. 1511 12

Regulation of epithelial cell proliferation and apoptosis are important determinants of colonic crypt homeostasis, and their dysregulations are key features of colon cancer. In this study, we investigated whether CD44, an adhesion protein overexpressed in colon cancer, plays a role in colonocyte proliferation and apoptosis, and the molecular mechanisms involved in these processes. Using a CD44 knockout mouse model devoid of a gross phenotype, we found that CD44 null colonocytes have alterations at the ultrastructural and molecular levels. Mitochondria in CD44 null colonocytes at the top of the crypt have disrupted cristae. The ratio of anti-apoptotic Bcl-xl to pro-apoptotic Bak was shifted toward apoptosis in CD44 null colon due to decreased Bcl-xl expression. Caspase 9 was upregulated and active in CD44 null colon. Its expression shifted from a location restricted to the top of the control crypts to the whole crypt axis in CD44 null colon. Caspase 3 was also activated in CD44 null colon suggesting that CD44 null colonocytes are apoptotic via the intrinsic pathway. Cell cycle regulators, cyclin A, p21, and pRb protein were abrogated in CD44 null mice. Overall, CD44 negatively regulates apoptosis via the mitochondrial pathway in the colonic epithelium through the regulators/effectors of cell cycle and apoptosis.
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PMID:CD44 negatively regulates apoptosis in murine colonic epithelium via the mitochondrial pathway. 1512 1

Overexpression of CD44, especially its variant isoforms, occurs consistently in colon cancer, as compared to autologous normal colon, and this change occurs also in most other types of cancer. One of the basic features of malignant transformation is the acquisition of resistance to apoptosis. In this study, we asked whether the expression of CD44 and some of its variant isoforms commonly found in colon cancer participate in resistance to apoptosis and what are the mechanisms involved. A human colon cancer cell line, SW620, which does not express CD44 was stably transfected with standard, v3-10, and v8-10 containing isoforms of CD44. Mock-transfected and CD44-transfected cells were exposed to etoposide to induce apoptosis. Apoptotic and concomitant changes relevant to the mechanisms of apoptosis were monitored by flow cytometry, DNA fragmentation, and immunoblot analyses. It was observed that resistance to apoptosis induced by etoposide is promoted by CD44 expression in SW620, and this resistance is better sustained by the full variant isoform, v3-10. Concomitant alterations in caspase 9, caspase 3, Bcl-xl, and Bak indicated that the resistance to apoptosis in this model involved the mitochondrial pathway. The differential response of CD44 transfectants was associated with a downregulation of pRb and phosphorylated AKT. The results of this study are consistent with the conclusion that expression of variant CD44 isoforms which is characteristic of colon cancer, and most other types of cancer, confers a selective advantage to resist apoptosis, thereby promoting cell transformation into a malignant phenotype, in conjunction with other anti-apoptotic factors.
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PMID:CD44 promotes resistance to apoptosis in human colon cancer cells. 1521 46

How dietary corn oil is involved in colon carcinogenesis and cancer development is poorly understood. The aim of this study was to investigate whether long-term dietary corn oil promotes colon cancer by inhibiting the tumor suppressor gene p53-mediated mitochondria-dependent apoptosis in azoxymethane (AOM)-treated rats. Male Sprague-Dawley rats were injected with AOM or with saline and fed on a basal diet or basal diet supplemented with 10% corn oil for 48 weeks. Colonic aberrant crypt foci (ACF) and tumors, including adenomas and carcinomas, were examined. Colonic apoptosis and cell proliferation were evaluated. Wild type (wt) p53 was analyzed using reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. In addition, Bcl-2, Bcl-xL, Bax, and Bak localized in the mitochondria were detected. Long-term dietary corn oil increased ACF in AOM-treated rats at 12 weeks and promoted colon cancer invasion at 48 weeks. Cancer invasion was not observed in the AOM-treated rats without dietary corn oil, although colon adenomas and cancers were detected. Apoptosis was decreased and cell proliferation was increased in the AOM-treated rats with dietary corn oil, compared with the AOM-treated rats with dietary basal diet. In these rats, mitochondrial wt p53 was significantly inhibited through decreased mitochondrial localization of wt p53 and increased cytosolic p53, resulting in the upregulation of Bcl-2 and Bcl-xL and the downregulation of Bak in the mitochondria. Results suggest that long-term dietary corn oil promotes AOM-induced colon cancer development partly by inhibiting the tumor suppressor gene p53-mediated mitochondria-dependent apoptosis.
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PMID:Dietary corn oil promotes colon cancer by inhibiting mitochondria-dependent apoptosis in azoxymethane-treated rats. 1552 37


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