Biomedical subjects

Jong-Wook Park

Publications and source records attributed to Jong-Wook Park.

At least 19 recordsLinked to original sources

PubMed2006

Acquired TRAIL resistance in human breast cancer cells are caused by the sustained cFLIP(L) and XIAP protein levels and ERK activation.

We established TRAIL-resistant MDA-231/TR cells from MDA-231 parent cells to understand the mechanism of TRAIL resistance in breast cancer cells. The selected TRAIL-resistant cells were cross-resistant to TNF-alpha/cycloheximide but remained sensitive to DNA-damage drugs such as oxaliplatin and etoposide. The expression levels of death receptors (DR4 and DR5), FADD, cIAP1, cIAP2, and Bcl-2 family were not changed in TRAIL-treated both cells. Significant down-regulation of XIAP and cFLIP was occurred after TRAIL treatment in MDA-231 cells whereas their levels were sustained in MDA-231/TR cells. TRAIL-mediated activation of ERK and JNK were also observed in parent MDA-231 cells but not in MDA-231/TR cells. However, TRAIL-resistant cells showed constitutive activation state after treatment with TRAIL. Pretreatment with PD98059 or transfection of MKK1-DN (dominant negative) expression vector attenuated TRAIL resistance in MDA-231/TR cells. Our findings provide the evidence that the sustained expression level of cFLIP(L) and XIAP protein and constitutive ERK activation may lead to acquired TRAIL resistance in breast cancer cells.

Breast Neoplasms↗

PubMed2006

ESE-3 transcription factor is involved in the expression of death receptor (DR)-5 through putative Ets sites.

The death receptor 5 (DR-5), a receptor for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), is critical for TRAIL-mediated apoptosis in various tumor cells. The ESE-3, a member of Ets transcription factors, regulates the expression of a variety of cellular genes by binding to purine-rich GGAA/T core sequence in cooperation with other transcription factors and co-factors. In this study, we demonstrate for the first time that ESE-3 regulates DR-5 expression through Ets binding sequences on the DR-5 promoter. Using a combination of the electrophoretic mobility shift assay and the luciferase reporter assay, we identified putative Ets sites responsible for ESE-3 transcriptional activity on the DR-5 promoter. In addition, we show the possible involvement of co-factors CBP and p300 in ESE-3-mediated DR-5 up-regulation.

Cell Line, Tumor↗

PubMed2006

Elevated gadd153/chop expression during resveratrol-induced apoptosis in human colon cancer cells.

Resveratrol (3,4',5-tri-hydroxystilbene), a natural phytoalexin found at high levels in grapes and red wine, has been shown to induce anti-proliferation and apoptosis of human cancer cell lines. Resveratrol-induced dose-dependent apoptotic cell death in colon carcinoma cells, as measured by FACS analysis and internucleosomal DNA fragmentation assays. We demonstrate for the first time that resveratrol induce CCAAT/enhancer-binding protein-homologous protein (CHOP). Resveratrol-induced CHOP mRNA (and also protein) expression was inhibited by JNK specific inhibitor, but not ERK, p38 MAPK, PI3K and NF-kappaB inhibitors. Resveratrol-induced expression of CHOP involves the putative Sp1 site within the CHOP promoter region. Using a combination of the Sp1 cDNA transfection, the luciferase reporter assay and Sp1 inhibitor assay, we found that Sp1 site is required for resveratrol-mediated activation of the CHOP promoter. Suppression of CHOP expression by CHOP siRNA and treatment with mithramycin A attenuated resveratrol-induced apoptosis. Taken together, the present studies suggest that induction of CHOP protein may be involved, at least in part, in resveratrol-induced apoptosis.

Apoptosis↗

PubMed2006

Se-methylselenocysteine enhances PMA-mediated CD11c expression via phospholipase D1 activation in U937 cells.

CD11c/CD18 is expressed primarily on myeloid cells, where its expression is regulated both during differentiation and during monocyte maturation into tissue macrophages, and is also a receptor for fibrinogen and lipopolysaccharide (LPS). We focused on the molecular mechanisms leading to the activation of CD11c expression in differentiating U937 cells. During phorbol myristate acetate (PMA)-induced differentiation of U937 cells, we found that the mRNA expression of CD11c was increased. Se-methylselenocysteine (Se-MSC) potentiated up-regulation of CD11c expression and its promoter activity and increased PLD1 activity without affecting the level of PLD1 protein in PMA-treated cells. To examine the regulation mechanism of PMA and Se-MSC on CD11c gene expression through the activation of PLD1, we analyzed changes in the CD11c mRNA level and the promoter activity following treatment of a selective PLD inhibitor n-butanol. The combinatory effect of PMA and Se-MSC on CD11c gene expression was abolished by n-butanol in a dose-dependent manner. Further, introduction of PLD1 gene into U937 cells increased CD11c mRNA expression and activated CD11c promoter activity in a dose-dependent manner. These results showed that Se-MSC increased PMA-induced CD11c expression through the activation of PLD1 signaling pathway. To our knowledge, this is the first report that expression of the CD11c gene is regulated by PLD1 and is enhanced by Se-MSC during PMA-induced U937 differentiation.

CD11c Antigen↗

PubMed2006

Curcumin sensitizes tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis through CHOP-independent DR5 upregulation.

Death receptor DR5 (DR5/TRAIL-R2) is an apoptosis-inducing membrane receptor for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). In this study, we showed that curcumin, a plant product containing the phenolic phytochemical, is a potent enhancer of TRAIL-induced apoptosis through upregulation of DR5 expression. Both treatment with DR5/Fc chimeric protein and silencing of DR5 expression using small interfering RNA (siRNA) attenuated curcumin plus TRAIL-induced apoptosis, showing that the critical role of DR5 in this cell death. Curcumin also induced the expression of a potential pro-apoptotic gene, C/EBP homologous protein (CHOP), both at its mRNA and protein levels. However, suppression of CHOP expression by small interfering RNA did not abrogate the curcumin-mediated induction of DR5 and the cell death induced by curcumin plus TRAIL, demonstrating that CHOP is not involved in curcumin-induced DR5 upregulation. Taken together, the present study demonstrates that curcumin enhances TRAIL-induced apoptosis by CHOP-independent upregulation of DR5.

Acetylcysteine↗

PubMed2006

Differential inhibitory effects of baicalein and baicalin on LPS-induced cyclooxygenase-2 expression through inhibition of C/EBPbeta DNA-binding activity.

To evaluate the possible mechanisms responsible for the anti-inflammatory effects of baicalein or baicalin, lipopolysaccharide (LPS)-induced inflammatory responses in cultured Raw 264.7 cells were studied. In the present study, baicalein and baicalin, a flavonoid present in the root of Scutellaria baicalensis Georgi, were examined for their effects on LPS-induced cyclooxygenase-2 (COX-2) gene expression in Raw 264.7 macrophages. Baicalein, but not baicalin, inhibited COX-2 gene expression in LPS-induced Raw 264.7 cells. However, both polyphenolic compounds inhibited LPS-induced inducible nitric oxide synthase (iNOS) protein expression, iNOS mRNA expression, and NO production in a dose-dependent manner. To investigate the mechanism by which baicalein inhibits COX-2 gene expression, we examined activation of mitogen-activated protein kinases (MAPKs) in Raw 264.7 cells. We did not observe any significant change in the phosphorylation of MAPKs between baicalein- and baicalin-treated cells. Baicalein and baicalin had no effect on LPS-induced nuclear factor-kappaB (NF-kappaB) and cAMP response element binding protein (CREB) DNA binding activity. Baicalein, but not baicalin, significantly inhibited the DNA binding activity of CCAAT/enhancer binding protein beta (C/EBPbeta) These results indicated that differential effects of baicalein and baicalin on COX-2 gene expression in LPS-induced Raw 264.7 cells were mediated through inhibition of C/EBPbeta DNA binding activity. Taken together, these results suggest that baicalein acts to inhibit inflammation through inhibition of COX-2 gene expression through blockade of C/EBPbeta DNA binding activity.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2006

Proteasome inhibitor-induced cyclooxygenase-2 expression in Raw264.7 cells is potentiated by inhibition of c-Jun N-terminal kinase activation.

Prostaglandins play regulatory roles in a variety of physiological and pathological processes in immune response and inflammation. MG132, proteasome inhibitor, is known to anti-tumor agent activity and anti-inflammation with inhibitory property of NF-kappaB. We investigated the effect of MG132 on the expression of cyclooxygenase-2 (COX-2), the rate-limiting enzyme in the synthesis of PGE(2), using macrophage cell line, Raw264.7. Our results showed that COX-2 expression is up-regulated by MG132 treatment and that this induction of COX-2 is regulated in part at the transcriptional level. In addition, we demonstrated the signal transduction pathway of mitogen-activated protein kinase (MAP kinase) in MG132-induced COX-2 expression. The p38 MAPK inhibitor (SB 203580) prevented MG132-induced COX-2 expression, whereas c-Jun N-terminal kinase (JNK) inhibitor (SP 600125) and MAPK kinase 4 (MKK4)-DN (dominant negative mutant) and MKK7-DN significantly enhanced COX-2 expression. These results suggest that MG132-induced COX-2 expression is associated with the activation of p38 MAPK and the inhibition of JNK signaling pathways.

Animals↗

PubMed2006

Desferrioxamine, an iron chelator, enhances HIF-1alpha accumulation via cyclooxygenase-2 signaling pathway.

Cyclooxygenase-2 (COX-2) is an important inducible enzyme in inflammation and is overexpressed in a variety of cancers. Evidence is rapidly accumulating that chronic inflammation may contribute to carcinogenesis through increase of cell proliferation, angiogenesis, and metastasis in a number of neoplasms, including colorectal carcinoma. In the present study, we investigated some mechanistic aspects of DFX-induced hypoxia-driven COX-2 expression. Desferrioxamine (DFX), an iron chelator, is known to upregulate inflammatory mediators. DFX induced the expression of COX-2 and accumulation of HIF-1alpha protein in dose-dependent manners, but hypoxia mimetic agent cobalt chloride (CoCl2) induced accumulation of HIF-1alpha protein but not increase of COX-2 expression. DFX-induced increase of COX-2 expression and HIF-1alpha protein level was attenuated by addition of ferric citrate. This result suggested that the iron chelating function of DFX was important to induce the increase of COX-2 and HIF-1alpha protein. PD98059 significantly inhibited the induction of COX-2 protein and accumulation of HIF-1alpha, suggesting that DFX-induced increase of HIF-1alpha and COX-2 protein was mediated, at least in part, through the ERK signaling pathway. In addition, pretreatment with NS-398 to inhibit COX-2 activity also effectively suppressed DFX-induced HIF-1alpha accumulation in human colon cancer cells, providing the evidence that COX-2 plays as a regulator of HIF-1alpha accumulation in DFX-treated colon cancer cells. Together, our findings suggest that iron metabolism may regulate stabilization of HIF-1alpha protein by modulating cyclooxygenase-2 signaling pathway.

Colonic Neoplasms↗

PubMed2006

Thimerosal induces apoptosis and G2/M phase arrest in human leukemia cells.

Thimerosal is an organomercury compound with sulfhydryl-reactive properties. The ability of thimerosal to act as a sulfhydryl group is related to the presence of mercury. Due to its antibacterial effect, thimerosal is widely used as preservatives and has been reported to cause chemically mediated side effects. In the present study, we showed that the molecular mechanism of thimerosal induced apoptosis in U937 cells. Thimerosal was shown to be responsible for the inhibition of U937 cells growth by inducing apoptosis. Treatment with 2.5-5 microM thimerosal but not thiosalicylic acid (structural analog of thimerosal devoid of mercury) for 12 h produced apoptosis, G(2)/M phase arrest, and DNA fragmentation in a dose-dependent manner. Treatment with caspase inhibitor significantly reduced thimerosal-induced caspase 3 activation. In addition, thimerosal-induced apoptosis was attenuated by antioxidant Mn (III) meso-tetrakis (4-benzoic acid) porphyrin (Mn-TBAP). These data indicate that the cytotoxic effect of thimerosal on U937 cells is attributable to the induced apoptosis and that thimerosal-induced apoptosis is mediated by reactive oxygen species generation and caspase-3 activation.

Apoptosis↗

PubMed2006

Caspase-dependent and caspase-independent apoptosis induced by evodiamine in human leukemic U937 cells.

Evodiamine is one of the major bioactive compounds that have been isolated and purified from the fruit of Evodiae fructus. Evodiamine exhibits antitumor activities against the human tumor cells, including multidrug-resistant tumor cells. However, the molecular mechanism involved in cell death induced by evodiamine treatment remains poorly understood. In the present study, we showed that evodiamine activated the caspase-dependent apoptotic pathway. This apoptosis was only partially inhibited by a pancaspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, which suggested that evodiamine-induced apoptosis in leukemic U937 cells is partially caspase independent. We observed the nuclear translocation of apoptosis-inducing factor in evodiamine-induced apoptosis of U937 cells, which may be responsible for the caspase-independent apoptotic execution. We next showed that evodiamine induced the substantial amount of apoptosis both in Bcl-2- and Akt-overexpressing U937 cells but not in human peripheral blood mononuclear cells. Although benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone inhibited caspase activity in Bcl-2-overexpressing U937 cells, it completely prevented neither the induction of apoptosis or the nuclear translocation of apoptosis-inducing factor, which suggests that evodiamine is, at least in part, able to bypass the resistance of leukemia cells via caspase-independent apoptotic pathways. Thus, therapeutic strategy using evodiamine may warrant further evaluation.

Apoptosis↗

PubMed2006

Mithramycin A sensitizes cancer cells to TRAIL-mediated apoptosis by down-regulation of XIAP gene promoter through Sp1 sites.

Mithramycin A is a DNA-binding antitumor agent, which has been clinically used in the therapies of several types of cancer and Paget's disease. In this study, we investigated the combined effect of mithramycin A and tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) on apoptosis of cancer cells. In Caki renal cancer cells, which are resistant to TRAIL, cotreatment with subtoxic doses of mithramycin A and TRAIL resulted in a marked increase in apoptosis. This combined treatment was also cytotoxic to Caki cells overexpressing Bcl-2 but not to normal mesengial cells. Moreover, apoptosis by the combined treatment with mithramycin A and TRAIL was dramatically induced in various cancer cell types, thus offering an attractive strategy for safely treating malignant tumors. Mithramycin A-stimulated TRAIL-induced apoptosis was blocked by pretreatment with the broad caspase inhibitor zVAD-fmk or Crm-A overexpression, showing its dependence on caspases. We found that mithramycin A selectively down-regulated XIAP protein levels in various cancer cells. Luciferase reporter assay and the chromatin immunoprecipitation assay using the XIAP promoter constructs show that mithramycin A down-regulates the transcription of XIAP gene through inhibition of Sp1 binding to its promoter. Although XIAP overexpression significantly attenuated apoptosis induced by mithramycin A plus TRAIL, suppression of XIAP expression by transfection with its small interfering RNA prominently enhanced TRAIL-induced apoptosis. We present here for the first time that mithramycin A-induced suppression of XIAP transcription plays a critical role in the recovery of TRAIL sensitivity in various cancer cells.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2006

Age-related differential growth rate and response to 4-hydroxynonenal in mouse aortic smooth muscle cells.

4-Hydroxynonenal (4-HNE) is a peroxidation product of omega-6-poly-unsaturated fatty acids and exerts growth modifying as well as cytotoxic activities. This aldehyde component of oxidized lipid is increased during the aging process. In this study, to characterize the potential role of the lipid peroxidation product in aging, we studied the effects of 4-HNE on cell proliferation and activation of cell-cycle machinery and the mitogen-activated protein kinase signaling pathway. 4-HNE-treated smooth muscle cells (SMCs) have shown a different cell proliferation rate depending on 4-HNE's incubation time and concentration. Interestingly, a prolonged treatment of 0.1 microM 4-HNE (36 h) resulted in an increase of cell growth in young SMCs but displayed cytotoxicity in aged SMCs. Treatment with 4-HNE enhanced cyclin D1 expression and activation of the extracellular signal-regulated kinase (ERK) signaling pathway, which were stronger in young SMCs compared with aged SMCs. Moreover, 4-HNE-induced cell proliferation and cyclin D1 expression were significantly attenuated by PD98059, the ERK inhibitor, in young SMCs. These data clearly indicate that increased cell proliferation was associated with the induction of cyclin D1 expression which was regulated by ERK in 4-HNE-treated young SMCs for 36 h. In contrast, we found that the cytotoxicity of aged SMCs to 4-HNE was partly related to generation of ROS and that pretreatment with N-acetyl-L-cysteine prevented 4-HNE-induced cell death in aged SMCs. These results suggest that the prolonged treatment of 0.1 microM 4-HNE-induced cell growth inhibition was caused by generation of ROS. Collectively, the age-related different growth rates and responses to 4-HNE are related to the expression level of cyclin D1, activation of the ERK signaling pathway, and regulation of ROS generation in SMCs.

Acetylcysteine↗

PubMed2006

Leptomycin B, a metabolite of Streptomyces, inhibits the expression of inducible nitric oxide synthase in BV2 microglial cells.

Overexpression of inducible nitric oxide synthase (iNOS) and the resultant overproduction of NO has been implicated in neuronal inflammatory diseases. Leptomycin B (LMB), a metabolite of Streptomyces, has been identified as a specific inhibitor of CRM1 nuclear export receptor. In this study, we evaluated the effect of LMB on lipopolysaccharide (LPS)-induced iNOS expression in BV2 cells, a murine microglial cells and the associated mechanisms. LMB strongly inhibited LPS-induced iNOS protein and mRNA expressions in BV2 cells in which 10 ng/ml of LMB (18 nM) was sufficient to greatly down-regulate iNOS by LPS, suggesting the potency of LMB to inhibit iNOS. The data of iNOS promoter-driven luciferase assay further suggested that the LMB inhibitory effect was in part due to inhibition of iNOS transcription. However, LPS-induced activation of various intracellular signaling proteins, such as nuclear factor-kappaB (NF-kappaB), extracellular signal-regulated kinases (ERKs), p38s, and c-Jun N-terminal kinases (JNKs), whose activations are known to be important for iNOS expression by LPS in BV2 cells, were not affected in the presence of LMB. Together, these results suggest that LMB inhibits iNOS expression in response to LPS in BV2 microglia, and the inhibition seems to be associated with blockage of CRM1-mediated iNOS mRNA nuclear export and also in part transcriptional down-regulation of iNOS, but not through modulation of NF-kappaB and the mitogen-activated protein kinase signaling pathways.

Active Transport, Cell Nucleus↗

PubMed2005

Quercetin arrests G2/M phase and induces caspase-dependent cell death in U937 cells.

Quercetin, a natural product derived from grapes, has been shown to prevent carcinogenesis in murine models. We report here that quercetin induces anti-proliferation and arrests G2/M phase in U937 cells. The G2/M phase accumulation was accompanied by an increase in the level of the cyclin B. In contrast, the level of the cyclin D, cyclin E, E2F1, and E2F2 was marked decreased in quercetin-treated U937 cells. Removal of quercetin from the culture medium stimulates U937 cells to synchronously re-enter the cell cycle, decrease expression level of cyclin B, and increased the expression level of cyclin D and cyclin E. These data demonstrate that quercetin causes reversible G2/M phase arrest, which was related with dramatic changes in the level of cyclin B, cyclin D, and cyclin E. Quercetin-induced down-regulation of cyclin D and cyclin E was associated with suppression of transcriptional levels but not protein stability. In addition, quercetin-treated U937 cells showed DNA fragmentation, increased sub-G1 population, and generated a 60kDa cleavage product of PLC-gamma1 in a dose-dependent manner, which were significantly inhibited by z-VAD-fmk. These data clearly indicate that quercetin-induced apoptosis is associated with caspase activation. In summary, the growth inhibition of the quercetin is highly related to cell cycle arrest at the G2/M phase and induction of caspase-dependent apoptosis in human promonocytic U937 cells.

Apoptosis↗

PubMed2005

Arsenic trioxide induces Hsp70 expression via reactive oxygen species and JNK pathway in MDA231 cells.

In the present study, we determined the molecular pathways that induce the heat shock proteins (Hsps) after treatment of cells with arsenic trioxide. Administration of arsenic trioxide to MDA231 cells leads to induce Hsp70, which is accompanied by generation of reactive oxygen species (ROS) and activation of c-Jun N-terminal kinase (JNK). We showed that arsenic trioxide-induced Hsp70 expression was caused by activation of ROS and prevented by the antioxidant N-Acetyl-Cysteine (NAC). SP600125 and dominant-negative SEK suppressed Hsp70 promoter-driven reporter gene expression, suggesting that JNK would be preferentially associated with the protective heat shock response against arsenic trioxide stress. In addition, SP600125, a specific JNK inhibitor, significantly reduced the amount of phosphorylated HSF1 upon administration of arsenic trioxide. It is likely that Hsp70 expression against arsenic trioxide exposure protects cells from oxidative injury and apoptotic cell death by means of JNK activity.

Acetylcysteine↗

PubMed2005

Activation of human cancer/testis antigen gene, XAGE-1, in tumor cells is correlated with CpG island hypomethylation.

Expression of the XAGE-1 antigen is restricted to germ cells of the testis and a variety of neoplastic tissues. To date, the molecular mechanism for regulating expression of this cancer/testis antigen gene has been unknown. To evaluate methylation as a potential mechanism for regulating expression of this gene, we first correlated gene methylation status (measured by sequencing of bisulfide-modified DNA and COBRA) to expression of XAGE-1 mRNA in normal and cancerous cells. This analysis revealed dense methylation of the CpG island in the XAGE-1 gene promoter for the normal and cancerous cells that do not express this gene but loss of this methylation in normal testis, cancer cell lines and the primary gastric cancers where the gene is highly expressed. Further supporting the role of methylation in regulating expression of XAGE-1 were observations that treatment of 2 heavily methylated cell lines, SNU620 and HT29, with 5'-aza-deoxycytidine resulted in demethylation of XAGE-1 promoter and corresponding expression of this gene. Finally, we cloned various segments of the CpG-rich XAGE-1 gene promoter linked to a luciferase reporter construct and transiently transfected this construct into HCT116 cells. These experiments confirmed transcriptional regulatory activity for the promoter region that incorporates the CpG island and demonstrated that in vitro methylation of this island results in loss of promoter activity. Collectively, these studies indicate that XAGE-1 expression in normal and cancerous tissues is regulated by methylation of the CpG island in the gene promoter.

Antigens, Neoplasm↗

PubMed2005

The melanoma antigen gene as a surveillance marker for the detection of circulating tumor cells in patients with breast carcinoma.

BACKGROUND: Circulating occult tumors cells could be used for the surveillance of metastases after primary breast carcinoma therapy, but their detection is limited by the lack of specific molecular markers. Melanoma antigen genes (MAGEs), which are expressed in malignant tissues but not in normal tissues (except for placenta and testis), might provide such a marker. To date, however, the use of MAGEs in the detection of occult tumor cells using reverse transcription-polymerase chain reaction (RT-PCR) has been limited because of the heterogeneity and low expression of individual MAGEs in tumor tissues. METHODS: We developed multiple MAGE-recognizing primers (MMRPs) that were capable of binding to the cyclic DNA of 6 MAGE-A gene subtypes (MAGE-A1-MAGE-A6). We assessed the ability of the MMRPs to detect the expression of MAGE-A gene subtypes in peripheral blood obtained from patients with benign or malignant breast disease. RESULTS: MAGE-A gene expression was not detected in 32 patients with benign disease but was detected in 1 of 31 patients (3%) patients with negative lymph node breast carcinoma, in 10 of 52 patients (19%) with 1-3 positive lymph nodes, in 11 of 53 patients (21%) with > or = 4 positive lymph nodes, and in 20 of 52 patients (39%) with metastatic disease. The results were statistically significant (P < 0.0001; chi-square test for linear-by-linear association). The results also showed that the detection of MAGE-A gene expression in the blood predicted tumor progression or recurrence. CONCLUSIONS: The results suggested that MAGE-A gene expression may be used for the surveillance of circulating breast carcinoma cells after primary therapy by RT-nested PCR using MMRPs.

Adult↗

PubMed2005

Curcumin sensitizes tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through reactive oxygen species-mediated upregulation of death receptor 5 (DR5).

Curcumin exhibits anti-inflammatory and antitumor activities. Although its functional mechanism has not been elucidated so far, numerous studies have shown that curcumin induces apoptosis in cancer cells. In the present study, we show that subtoxic concentrations of curcumin sensitize human renal cancer cells to the tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis. This apoptosis induced by the combination of curcumin and TRAIL is not interrupted by Bcl-2 overexpression. We found that treatment with curcumin significantly induces death receptor 5 (DR5) expression both at its mRNA and protein levels, accompanying the generation of the reactive oxygen species (ROS). Not only the pretreatment with N-acetylcystine but also the ectopic expression of peroxiredoxin II, an antioxidative protein, dramatically inhibited the apoptosis induced by curcumin and TRAIL in combination, blocking the curcumin-mediated DR5 upregulation. Taken together, the present study demonstrates that curcumin enhances TRAIL-induced apoptosis by ROS-mediated DR5 upregulation.

Antineoplastic Agents↗