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PubMed2006

Overexpression of hRFI inhibits 5-fluorouracil-induced apoptosis in colorectal cancer cells via activation of NF-kappaB and upregulation of BCL-2 and BCL-XL.

Resistance to apoptosis is one of the important determinants of resistance to 5-fluorouracil (5-FU) in colorectal cancer cells. Human Ring-Finger homologous to Inhibitor of apoptosis protein type (hRFI) is a newly discovered gene that has been shown to inhibit death receptor-mediated apoptosis in colorectal cancer cells. However, the molecular mechanism of the inhibition of apoptosis is presently unknown. In order to investigate the molecular function of hRFI in the regulation of 5-FU-induced apoptosis in colorectal cancer cells, HCT116 cells were stably transfected with hRFI or LacZ as a control. hRFI overexpression resulted in cellular resistance to 5-FU through an inhibition of the mitochondrial apoptotic pathway and specific upregulation of Bcl-2 and Bcl-XL. Futhermore, hRFI overexpression resulted in the activation of nuclear factor-kappaB (NF-kappaB). Inhibition of NF-kappaB effectively reversed the resistance to apoptosis as well as the upregulation of Bcl-2 and Bcl-XL in the hRFI transfectant, indicating that the activation of NF-kappaB is the key mechanism for all these findings. Overexpression of hRFI in SW480 and COLO320 colorectal cancer cells similarly resulted in resistance to 5-FU with the activation of NF-kappaB and upregulation of Bcl-2 and Bcl-XL. hRFI might be a novel therapeutic target for gene therapy in colorectal cancer.

Antimetabolites, Antineoplastic↗

PubMed2005

Live cell catapulting and recultivation does not change the karyotype of HCT116 tumor cells.

We used laser microdissection and pressure catapulting (LMPC) to isolate and subsequently recultivate cells from the colorectal cancer cell line HCT116. Cell isolation and recultivation was repeated 5 times from the preceding cell culture. The chromosomal composition of the HCT116 cells was analyzed at the beginning and after each recultivation. We did not observe any additional chromosomal structural or copy number changes during this procedure. Our data suggest that the procedure of cell isolation by LMPC and subsequent recultivation does not affect the karyotype of the respective cells. This technology will facilitate the analysis of different cell populations in a heterogeneous tumor cell population.

Cell Culture Techniques↗

PubMed2005

Effect of caffeic acid phenethyl ester on proliferation and apoptosis of colorectal cancer cells in vitro.

AIM: To study the effect of caffeic acid phenethyl ester (CAPE) on proliferation, cell cycle, apoptosis and expression of beta-catenin in cultured human colorectal cancer (CRC) cell line HCT116. METHODS: HCT116 cells were treated with CAPE at serial concentrations of 80, 40, 20, 10, 5, 2.5 mg/L. The proliferative status of HCT116 cells was measured by using methabenzthiazuron (MTT) assay. Cell cycle was analyzed by using flow cytometry (FCM) with propidium iodide (PI) labeling method. The rate of apoptosis was detected by using FCM with annexin V-FITC and PI double labeling method. beta-catenin levels were determined by Western blotting. beta-catenin localization in HCT116 was determined by indirect immunofluorescence. RESULTS: After HCT116 cells were exposed to CAPE (80, 40, 20, 10, 5, and 2.5 mg/L) for 24, 48, 72, 96 h, CAPE displayed a strong growth inhibitory effect in a dose- and time-dependent manner against HCT116 cells. FCM analysis showed that the ratio of G(0)/G(1) phase cells increased, S phase ratio decreased and apoptosis rate increased after HCT116 cells were exposed to CAPE (10, 5, and 2.5 mg/L) for 24 h. CAPE treatment was associated with decreased cytoplasmic beta-catenin, nuclear beta-catenin and a concurrent increase in beta-catenin protein expression at cell-cell junctions. CONCLUSION: CAPE could inhibit HCT116 cell proliferation and induce cell cycle arrest and apoptosis. Decreased beta-catenin protein expression may mediate the anti-proliferative effects of CAPE.

Apoptosis↗

PubMed2002

Docosahexaenoic acid suppresses the activity of peroxisome proliferator-activated receptors in a colon tumor cell line.

Fatty acids are generally considered as agonists for peroxisome proliferator-activated receptors (PPARs). Fatty acids have been shown to bind to and transactivate PPARs; it is not known whether fatty acids act as generalized agonists for PPARs in different cell types, and thus, stimulate the expression of PPAR-regulated target genes. Here, we investigated the potency of unsaturated fatty acids on transactivation of PPRE, DNA-binding activity of PPARs, and the expression of a PPAR-regulated gene product, CD36. Docosahexaenoic acid (DHA) suppressed the basal and PPAR agonist-induced transactivation of PPRE, and DNA binding of PPARs in colon tumor cells (HCT116). The suppression of PPAR transactivation by DHA leads to reduced expression of CD36 in HCT116 cells and human monocytic cells (THP-1) as determined by promoter reporter gene assay and flow cytometric analysis. Our results demonstrate that DHA and other unsaturated fatty acids act as antagonists instead of agonists for transactivation of PPRE and PPAR-regulated gene expression in the cell lines tested. These results suggest that PPAR-mediated gene expression and cellular responses can be dynamically modulated by different types of dietary fatty acids consumed.

Binding Sites↗

PubMed2005

Indomethacin suppresses growth of colon cancer via inhibition of angiogenesis in vivo.

AIM: It has been reported that regular consumption of nonsteroidal anti-inflammatory drugs like indomethacin decreases the incidence and mortality rate of a number of gastrointestinal cancers. We aimed to explore the efficacy and possible mechanisms of indomethacin on tumor growth and tumor angiogenesis of human colon cancer xenografts in nude mice. METHODS: MTT (thiazolyl blue) assay was used to assess the effect of indomethacin on cultured human colorectal cancer cell line HCT116. HCT116 cells were inoculated subcutaneously into BALB/c-nu/nu mice. After oral administration of indomethacin, 3 mg/kg.d for 4 wk, animals were sacrificed by cervical dislocation. Immunohistochemical staining was employed to determine the microvessel density (MVD) and vascular endothelial growth factor (VEGF) expression in tumor tissues. RESULTS: Indomethacin, a non-selective COX inhibitor, significantly decreased the viability of HCT116 cells in a dose-dependent manner (P<0.05) with 50% inhibition at approximately 318.2+/-12.7 mumol/L. Growth of HCT116 cell tumor was significantly suppressed by indomethacin. The tumor volume was significantly decreased in the treated group (458.89+/-32.07 mm(3)) compared to the control group (828.21+/-31.59 mm(3)) (P<0.05). The MVD of the treated group (19.50+/-5.32) was markedly decreased compared to the control group (37.40+/-4.93) (P<0.001). The VEGF expression of the treated group (1.19+/-0.17) was obviously reduced as compared to the control group (1.90+/-0.48) (P<0.01). The decrease in MVD was positively correlated with the decrease of VEGF expression (r(s) = 0.714, P<0.05). We did not see gastrointestinal complications in the treated group and no differences were noted in the body weight of the mice between the two groups throughout the study (P>0.05). CONCLUSION: Indomethacin can significantly decrease the viability of cultured HCT116 cells and retard human colorectal HCT116 cell tumor growth via inhibiting tumor angiogenesis, which might be through reduction of VEGF expression.

Angiogenesis Inhibitors↗

PubMed1998

Regulation of transforming growth factor alpha expression in a growth factor-independent cell line.

Aberrant transcriptional regulation of transforming growth factor alpha (TGF alpha) appears to be an important contributor to the malignant phenotype and the growth factor independence with which malignancy is frequently associated. However, little is known about the molecular mechanisms responsible for dysregulation of TGF alpha expression in the malignant phenotype. In this paper, we report on TGF alpha promoter regulation in the highly malignant growth factor-independent cell line HCT116. The HCT116 cell line expresses TGF alpha and the epidermal growth factor receptor (EGFR) but is not growth inhibited by antibodies to EGFR or TGF alpha. However, constitutive expression of TGF alpha antisense RNA in the HCT116 cell line resulted in the isolation of clones with markedly reduced TGF alpha mRNA and which were dependent on exogenous growth factors for proliferation. We hypothesized that if TGF alpha autocrine activation is the major stimulator of TGF alpha expression in this cell line, TGF alpha promoter activity should be reduced in the antisense TGF alpha clones in the absence of exogenous growth factor. This was the case. Moreover, transcriptional activation of the TGF alpha promoter was restored in an antisense-TGF alpha-mRNA-expressing clone which had reverted to a growth factor-independent phenotype. Using this model system, we were able to identify a 25-bp element within the TGF alpha promoter which conferred TGF alpha autoregulation to the TGF alpha promoter in the HCT116 cell line. In the TGF alpha-antisense-RNA-expressing clones, this element was activated by exogenous EGF. This 25-bp sequence contained no consensus sequences of known transcription factors so that the TGF alpha or EGF regulatory element within this 25-bp sequence represents a unique element. Further characterization of this 25-bp DNA sequence by deletion analysis revealed that regulation of TGF alpha promoter activity by this sequence is complex, as both repressors and activators bind in this region, but the overall expression of the activators is pivotal in determining the level of response to EGF or TGF alpha stimulation. The specific nuclear proteins binding to this region are also regulated in an autocrine-TGF alpha-dependent fashion and by exogenous EGF in EGF-deprived TGF alpha antisense clone 33. This regulation is identical to that seen in the growth factor-dependent cell line FET, which requires exogenous EGF for optimal growth. Moreover, the time response of the stimulation of trans-acting factor binding by EGF suggests that the effect is directly due to growth factor and not mediated by changes in growth state. We conclude that this element appears to represent the major positive regulator of TGF alpha expression in the growth factor-independent HCT116 cell line and may represent the major site of transcriptional dysregulation of TGF alpha promoter activity in the growth factor-independent phenotype.

Cell Division↗

PubMed2005

Induction of apoptosis by R-flurbiprofen in human colon carcinoma cells: involvement of p53.

R-flurbiprofen, a non cyclooxygenase inhibiting non-steroidal anti-inflammatory drug (NSAID), has been found to inhibit tumor growth in various animal models. In vitro experiments have shown that this effect is based on the induction of a cell cycle block and apoptosis. Cell cycle inhibition has been explained by activation of the c-Jun-N-terminal kinase (JNK) and downregulation of cyclin D1 expression. However, the molecular mechanism leading to apoptosis is unknown. Here, we show that treatment of the human colon carcinoma cell line HCT116 with different concentrations of R-flurbiprofen leads to an accumulation of p53 protein which is accompanied by an increase in phosphorylated p53 at serine 15. Mutation of serine 15 to alanine by site directed mutagenesis and overexpression of the mutated p53 gene in HCT116 cells, revealed that these cells are significantly less sensitive to apoptosis induced by R-flurbiprofen than pcDNA control cells, as measured by PARP-cleavage and flow cytometry. By contrast, no difference was detected between HCT116p53ser15ala cells and HCT116 pcDNA cells with respect to induction of a cell cycle block after R-flurbiprofen treatment. Moreover, in nude mice HCT116p53ser15ala overexpressing xenografts were significantly less sensitive to R-flurbiprofen than HCT116 pcDNA control xenografts. In conclusion, we were able to show that induction of apoptosis in HCT116 cells after R-flurbiprofen treatment is at least partly dependent on the tumor suppressor gene p53 and that mutation of p53 at serine 15 impairs the apoptotic potency of R-flurbiprofen.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2002

CXCR4-dependent HIV-1 infection of differentiated epithelial cells.

Epithelial cells constitute a physical barrier to sexual transmission of HIV, but are also a source of cytokines that could alter infection efficiency. We studied HIV infection of the human colonic epithelial cell line HCT116, which is a model for differentiation of intestinal mucosal epithelium. Differentiated HCT116 cells had increased expression of cell surface C-X-C chemokine receptor type-4 (CXCR4) that mediated HIV entry, despite the apparent absence of cell surface CD4. HIV infection in differentiated HCT116 cells increased the levels of IL-1alpha, and IFN-alpha mRNA even though only 1% of cells had integrated provirus. The inefficient, CXCR4-mediated infection of differentiated HCT116 cells supports the view that epithelial cells are a barrier and not a portal for HIV transmission. However, low level infection of epithelial cells could trigger the release of cytokines that indirectly increase the transmission rate.

Cell Differentiation↗

PubMed2005

Two-dimensional polyacrylamide gel electrophoresis analysis of indomethacin-treated human colon cancer cells.

AIM: To establish the two-dimensional gel electrophoresis (2-DE) profiles of indomethacin (IN)-treated human colon cancer cell line HCT116, and to provide a new way to study its anti-tumor molecular mechanism through analyzing a variety of protein maps. METHODS: Two-DE profiles of HCT116 were established in IN-treated and untreated groups. Total proteins were separated by immobilized pH gradient-based 2-DE. The gels were stained by silver, scanned by ImageScanner, and analyzed with Image Master software. RESULTS: Clear background, well-resolved and reproducible 2-DE patterns of HCT116 cells were acquired in IN-treated and untreated group. The average deviation of spot position was 0.896+/-0.177 mm in IEF direction and 1.106+/-0.289 mm in SDS-PAGE direction respectively. In IN-treated group, 1169+/-36 spots were detected and 1061+/-32 spots were matched, the average matching rate was 90.6% in three gels. In untreated group, 1256+/-50 spots were detected and 1168+/-46 spots were matched, the average matching rate was 93.0% in three gels. Forty-five differential protein spots were displayed between IN-treated and untreated groups. Of which, 34 protein spots decreased and 9 showed higher expression in IN-treated group, and only two protein spots showed an expression in untreated cells. CONCLUSION: Two-DE profiles of IN-treated and untreated HCT116 cells were established. Apparent 45 different protein spots were detected in IN-treated and untreated HCT116 cells. The analysis on differential protein spots may serve as a new way to study the molecule mechanism of IN-treated colon cancer.

Antineoplastic Agents↗

PubMed2005

Proline oxidase, a proapoptotic gene, is induced by troglitazone: evidence for both peroxisome proliferator-activated receptor gamma-dependent and -independent mechanisms.

Proline oxidase (POX) is a redox enzyme localized in the mitochondrial inner membrane. We and others have shown that POX is a p53-induced gene that can mediate apoptosis through generation of reactive oxygen species (ROS). The peroxisome proliferator-activated receptor gamma (PPARgamma) ligand troglitazone was found to activate the POX promoter in colon cancer cells. PPARgamma ligands have been reported to induce apoptosis in a variety of cancer cells. In HCT116 cells expressing a wild-type PPARgamma, troglitazone enhanced the binding of PPARgamma to PPAR-responsive element in the POX promoter and increased endogenous POX expression. Blocking of PPARgamma activation either by antagonist GW9662 or deletion of PPAR-responsive element in the POX promoter only partially decreased the POX promoter activation in response to troglitazone, indicating also the involvement of PPARgamma-independent mechanisms. Further, troglitazone also induced p53 protein expression in HCT116 cells, which may be the possible mechanism for PPARgamma-independent POX activation, since POX has been shown to be a downstream mediator in p53-induced apoptosis. In HCT15 cells, with both mutant p53 and mutant PPARgamma, there was no effect of troglitazone on POX activation, whereas in HT29 cells, with a mutant p53 and wild type PPARgamma, increased activation was observed by ligand stimulation, indicating that both PPARgamma-dependent and -independent mechanisms are involved in the troglitazone-induced POX expression. A time- and dose-dependent increase in POX catalytic activity was obtained in HCT116 cells treated with troglitazone with a concomitant increase in the production of intracellular ROS. Our results suggest that the induction of apoptosis by troglitazone may, at least in part, be mediated by targeting POX gene expression for generation of ROS by POX both by PPARgamma-dependent and -independent mechanisms.

Anilides↗

PubMed2005

Characteristics of apoptosis in HCT116 colon cancer cells induced by deoxycholic acid.

Hydrophobic bile acids induce apoptosis in both colon cancer cells and hepatocytes. The mechanism by which colon cancer cells respond to bile acids is thought to be different from that of hepatocytes. Therefore, we investigated the characteristics of apoptosis in colon cancer cell line HCT116. Hydrophobic bile acids, i.e., deoxycholic acid (DCA), and chenodeoxycholic acid, induced apoptosis in HCT116 cells. Apoptotic indications were detectable at as early as 30 min and the extent increased in time- and concentration-dependent manners. SDS and a hydrophilic bile acid, cholic acid, did not induce apoptosis even at cytotoxic concentrations. Pretreatment with cycloheximide failed to inhibit apoptosis, suggesting that protein synthesis is not involved in the apoptotic response. Release of cytochrome c from mitochondria and activation of caspase-9 were detectable after 5 and 10 min, respectively, whereas remarkable activation of Bid was not detected. Ursodeoxycholic acid (UDCA) protected HCT116 cells from DCA-induced apoptosis but a preincubation period of > or =5 h was required. Nevertheless, UDCA did not inhibit cytochrome c release from mitochondria. Our results indicate that hydrophobic bile acids induce apoptosis in HCT116 cells by releasing cytochrome c from mitochondria via an undefined but specific mechanism, and that UDCA protects HCT116 cells by acting downstream of cytochrome c release.

Apoptosis↗

PubMed2006

Octahedral Pt(IV) complex K101 induces apoptosis via ERK1/2 activation and the p53 pathway in human colon cancer cells.

Recently, the synthesized octahedral Pt(IV) compound trans,cis-Pt(acetato)2Cl2(1,4-butanediamine), K101, showed potent anti-tumor activity in vitro and in vivo. For the further investigation of K101-induced anti-cancer activity, we tested cytotoxicity against various cancer cell lines and performed the histoculture drug response assay (HDRA) against human colorectal tumor tissues in vitro. We investigated the signaling pathway of K101-induced apoptosis via expression of p53 and ERK1/2 in the human colon cell line HCT116. The cytotoxicity and the three-dimensional HDRA of K101 were evaluated using the MTT assay. To study the K101-induced apoptosis pathway, we performed FACS analysis and immunoblotting of p53, p21, Bax, Fas and ERK1/2 in HCT116 cells treated with or without K101. The cytotoxic IC50 values of K101 ranged from 1.15 to 2.38 micromol/l, compared to cisplatin ranging from 2.13 to 13.1 micromol/l. Among several cancer cell lines, K101 showed greater potency than cisplatin in colon cancer cell lines. In the HDRA, K101 showed 80.0-91.4% efficacy rates compared with 48.6% for cisplatin against colorectal cancer patient tissues. In the signaling pathway, the expression of p53 and phospho-ERK1/2 was increased in a time-dependent manner by treatment with K101 in the HCT116 cells. When K101 was treated with MEK inhibitor U0126, the cell death rate was increased. The octahedral Pt(IV) complex K101 could be an attractive candidate as a chemotherapeutic agent against colon cancer. ERK1/2 activation and the p53 pathway may play significant functions in mediating K101-induced apoptosis in human colon cancer cells.

Antineoplastic Agents↗

PubMed2006

Potential of the Akt inhibitor LY294005 to antagonize the efficacy of Cisplatin against HCT116 tumor cells in a DNA mismatch repair-dependent manner.

Human colorectal adenocarcinoma sublines either deficient (HCT116+ch2) or proficient (HCT116+ch3) in the function of MLH1, one of five proteins crucial to DNA mismatch repair (MMR), were used to investigate whether the Akt-specific inhibitor LY294005 could not only increase the efficacy of platinum drugs in HCT116 cells in general but also increase the efficacy of the cisplatinum compounds Cisplatin and Lipoplatin specifically in MLH1-deficient, Cisplatin- and Lipoplatin-resistant HCT116 cells. We report that, under the conditions it increased the efficacy of Docetaxel and did not affect that of 6-thioguanine, LY294005 decreased the sensitivity of both sublines to Cisplatin, Lipoplatin, Oxaliplatin, and Lipoxal. Notably, the LY294005-imposed decrease was significantly higher in the MLH1-proficient than in the MLH1-deficient subline with Cisplatin and Lipoplatin, whereas it was nearly the same in both sublines with Oxaliplatin and Lipoxal. These LY294005-imposed changes in drug sensitivity, i.e. increase with Docetaxel and decreases with platinum compounds, were not associated with the concomitant abrogation in the levels of phospho-Aktser473. Analogous changes in drug sensitivity were also observed with the PI3-kinase inhibitor LY294002, but these changes were associated with complete abrogation of phospho-Aktser473. These observations suggest a possible relationship between MMR-mediated cisplatinum DNA damage signaling and the Akt signaling pathway, e.g. a common target for both pathways. A possibly novel property of Akt in aggravating drug sensitivity may also be proposed.

Adaptor Proteins, Signal Transducing↗

PubMed2001

Low concentrations of paclitaxel induce cell type-dependent p53, p21 and G1/G2 arrest instead of mitotic arrest: molecular determinants of paclitaxel-induced cytotoxicity.

Paclitaxel (PTX), a microtubule-active agent, blocks cell proliferation by inhibiting mitotic progression leading to mitotic and postmitotic arrest and cell death. Here we demonstrate for the first time that very low concentrations of PTX (3-6 nM) can completely inhibit cell proliferation without arresting cells at mitosis. At these low concentrations that are insufficient to inhibit mitotic progression, PTX induced both p53 and p21 causing G1 and G2 arrest in A549. In contrast, low PTX concentrations failed to induce G1 and G2 arrest in A549/E6 cells, that do not express p53. Furthermore, we observed that the levels of p53 and p21 induced by adriamycin and by low concentrations of PTX in A549 cells were comparable. This observation led us to conclude that low concentrations of PTX can induce p53 and p21 sufficiently to cause G1 and G2. Many other cell lines, including HCT116 cells, do not readily upregulate p53 in response to PTX, and therefore undergo exclusively mitotic and postmitotic arrest after PTX treatment. At low concentrations that do not cause mitotic arrest, PTX did not significantly inhibit proliferation of these cells. In HCT116 cells, loss of p53 (HCT/p53(-/-)) or p21 (HCT/p21(-/-)) affects both Bax and Bcl-2 expression. In cells lacking p53, levels of Bax and p21 were decreased. In cells lacking p21, levels of wt p53 were highly increased to compensate for the loss of p21. This in turn results in upregulation of Bax and downregulation of Bcl-2 resulting in an increase of the apoptotic Bax/Bcl2 ratio consistent with increased sensitivity of these cells to apoptotic stimuli. High levels of p53 and Bax/Bcl-2 ratio can also explain why loss of p21 is rarely found in human cancer.

Antineoplastic Agents, Phytogenic↗

PubMed2005

Nanosecond pulsed electric fields (nsPEF) induce direct electric field effects and biological effects on human colon carcinoma cells.

Nanosecond pulsed electric fields (nsPEFs) are ultrashort pulses with high electric field intensity (kV/cm) and high power (megawatts), but low energy density (mJ/cc). To determine roles for p53 in response to nsPEFs, HCT116 cells (p53+/+ and p53-/-) were exposed to nsPEF and analyzed for membrane integrity, phosphatidylserine externalization, caspase activation, and cell survival. Decreasing plasma membrane effects were observed in both HCT116p53+/+ and p53-/- cells with decreasing pulse durations and/or decreasing electric fields. However, addition of ethidium homodimer-1 and Annexin-V-FITC post-pulse demonstrated greater fluorescence in p53-/- versus p53+/+ cells, suggesting a postpulse p53-dependent biological effect at the plasma membrane. Caspase activity was significantly higher than nonpulsed cells only in the p53-/- cells. HCT116 cells exhibited greater survival in response to nsPEFs than HL-60 and Jurkat cells, but survival was more evident for HCT116p53+/+ cells than for HCT116p53-/- cells. These results indicate that nsPEF effects on HCT116 cells include (1) apparent direct electric field effects, (2) biological effects that are p53-dependent and p53-independent, (3) actions on mechanisms that originate at the plasma membranes and at intracellular structures, and (4) an apparent p53 protective effect. NsPEF applications provide a means to explore intracellular structures and functions that can reveal mechanisms in health and disease.

Annexin A5↗

PubMed2006

Absence of p300 induces cellular phenotypic changes characteristic of epithelial to mesenchyme transition.

p300 is a transcriptional cofactor and prototype histone acetyltransferase involved in regulating multiple cellular processes. We generated p300 deficient (p300-) cells from the colon carcinoma cell line HCT116 by gene targeting. Comparison of epithelial and mesenchymal proteins in p300- with parental HCT116 cells showed that a number of genes involved in cell and extracellular matrix interactions, typical of 'epithelial to mesenchyme transition' were differentially regulated at both the RNA and protein level. p300- cells were found to have aggressive 'cancer' phenotypes, with loss of cell-cell adhesion, defects in cell-matrix adhesion and increased migration through collagen and matrigel. Although migration was shown to be metalloproteinase mediated, these cells actually showed a downregulation or no change in the level of key metalloproteinases, indicating that changes in cellular adhesion properties can be critical for cellular mobility.

Cell Adhesion↗

PubMed2004

[Correlation between sensitivity to TRAIL and expression level of DR5 on surface of tumor cells].

OBJECTIVE: To investigate the correlation between sensitivity to tumor necrosis factor-related apoptosis inducing ligand (TRAIL) and expression level of death receptor 5 (DR5) on tumor cell surface. METHODS: Anti-DR5 mAb was used to detect expression level of DR5 on surface of tumor cells by flow cytometry. Sensitivity to apoptosis induced by TRAIL was determined by TRAIL apoptosis kit. The correlation between expression level of DR5 and sensitivity to TRAIL was analyzed. RESULTS: The expression of DR5 on surface of tumor cells was approximately 97.9% in U937 cells, 95.1% in Jurkat cells, 93.8% in SW480 cells, 86.2% in HCT116 cells, 64.2% in HL-60 cells, 46.6% in HeLa cells and 13.1% in K562 cells, respectively. The apoptosis rate induced by TRAIL was 72.6% in U937 cells, 85.2% in Jurkat cells, 78.6% in SW480 cells, 70.2% in HCT116 cells, 60.1% in HL-60 cells, 45.4% in HeLa cells and 12.3% in K562 cells, respectively. There was a significant positive correlation between the expression level of DR5 with TRAIL-inducing apoptosis (r = 0.997, P < 0.001). CONCLUSION: TRAIL-inducing apoptosis is related to the expression level of DR5 on surface of tumor cells. The results confirm the importance of DR5 expression for induction of apoptosis by TRAIL.

Antibodies, Monoclonal↗

PubMed2004

Induction of p53-dependent apoptosis in HCT116 tumor cells by RNA viruses and possible implications in virus-mediated oncolysis.

Recent findings showed that type I interferons (IFN-alpha/beta) induce the transcription of tumor suppressor p53 and sensitize primary mouse embryonic fibroblasts (MEFs) to p53-mediated apoptosis by oncolytic viruses. However, the ability of RNA viruses to induce a p53-mediated apoptotic response may differ between primary and tumor cells and may be dependent upon the virus type. We have investigated this hypothesis by analyzing the apoptotic effects of various oncolytic viruses on the human colon carcinoma HCT116 cells and their derivatives lacking either p53 or bax gene. We show that HCT116 cells are resistant to the apoptotic effects of vesicular stomatitis virus, reovirus or poliovirus but activate the p53/Bax apoptotic pathway after infection with Sendai virus. These data substantiate the role of p53 in virus-mediated apoptosis and show that, unlike primary cells, tumor cells may be more selective in the activation of p53 pathway in response to the infection with specific types of viruses.

Apoptosis↗