Biomedical subjects

A Miyajima

Publications and source records attributed to A Miyajima.

At least 55 records · Page 3Linked to original sources

PubMed1999

CIS associates with the interleukin-2 receptor beta chain and inhibits interleukin-2-dependent signaling.

CIS is a cytokine-induced SH2-containing protein that was originally cloned as an interleukin (IL)-3-inducible gene. CIS is known to associate with the IL-3 receptor beta chain and erythropoietin receptor and to inhibit signaling mediated by IL-3 and erythropoietin. We now demonstrate that CIS also interacts with the IL-2 receptor beta chain (IL-2Rbeta). This interaction requires the A region of IL-2Rbeta (residues 313-382), which also mediates the association of IL-2Rbeta with Lck and Jak3. Correspondingly, CIS inhibits functions associated with both of these kinases: Lck-mediated phosphorylation of IL-2Rbeta and IL-2-mediated activation of Stat5. Thus, we demonstrate that CIS can negatively control at least two independent IL-2 signaling pathways. Although a functional SH2 binding domain of CIS was not required for its interaction with IL-2Rbeta in vitro, its phosphotyrosine binding capability was essential for the inhibitory action of CIS. On this basis, we have generated a mutant form of CIS protein with an altered SH2 domain that acts as a dominant negative and should prove useful in further understanding CIS action.

Amino Acid Sequence↗

PubMed1999

A novel oncostatin M-inducible gene OIG37 forms a gene family with MyD118 and GADD45 and negatively regulates cell growth.

Oncostatin M (OSM) is a member of the IL-6 family cytokines that use gp130 as a common signal transducer and exhibits both growth stimulatory as well as growth inhibitory activity depending on the cells. To analyze the mechanism of OSM function, we isolated immediate early responsive genes upon OSM stimulation. Here we describe the novel OSM-inducible gene OIG37 that is related to MyD118 and GADD45. The MyD118 gene has been described as an immediate early gene induced by IL-6 in M1 monocytic cells, and GADD45 was identified as a gene induced by UV or gamma-ray irradiation. Both are considered to function in growth arrest and/or DNA repair. Although the expression of OIG37, MyD118, and GADD45 was rather ubiquitous, it was differentially regulated. As the gp130 mutant defective for activating the STAT3 pathway showed the reduced induction of OIG37 by cytokine stimulation and expression of dominant negative STAT3 inhibited the induction of OIG37 by OSM, STAT3 is involved in OIG37 induction by IL-6 family cytokines. To examine the function of OIG37, we expressed it in NIH3T3 and IL-3-dependent BaF3 cells and found that OIG37 suppressed cell growth without any evidence of apoptosis. Whereas both MyD118 and OIG37 suppressed cell growth in both cell lines, suppression by OIG37 was more efficient than by MyD118. Immunoprecipitation experiments indicated that OIG37 associates with p21, a cyclin-dependent kinase inhibitor, and proliferating cell nuclear antigen.

Amino Acid Sequence↗

PubMed1999

Hepatic differentiation induced by oncostatin M attenuates fetal liver hematopoiesis.

Embryonic liver is a transient site for definitive hematopoiesis. Along with maturation of the bone marrow and spleen, hematopoietic cells relocate from the liver to their final destinations while the liver starts organizing its own structure and develops numerous metabolic functions toward adult. Recently, it was demonstrated that the signal exerted by oncostatin M (OSM) through gp130 plays a pivotal role in the maturation process of the liver both in vitro and in vivo. However, the molecular basis underlying the termination of embryonic hematopoiesis remains unknown. In this study, we report that primary culture of fetal hepatic cells from embryonic day 14.5 murine embryos supported expansion of blood cells from Lin-Sca-1(+)c-Kit+ cells, giving rise to myeloid, lymphoid, and erythroid lineages. Of interest, promotion of hepatic development by OSM and glucocorticoid strongly suppressed in vitro hematopoiesis. Consistent with these results, hepatic culture from the embryonic day 18.5 liver no longer supported hematopoiesis. These data together with the previous observations suggest that the signals exerted by OSM and glucocorticoid induce hepatic differentiation, which in turn terminate embryonic hematopoiesis and promote relocation of hematopoietic cells.

Animals↗

PubMed1999

Fetal liver development requires a paracrine action of oncostatin M through the gp130 signal transducer.

Fetal liver, the major site of hematopoiesis during embryonic development, acquires additional various metabolic functions near birth. Although liver development has been characterized biologically as consisting of several distinct steps, the molecular events accompanying this process are just beginning to be characterized. In this study, we have established a novel culture system of fetal murine hepatocytes and investigated factors required for development of hepatocytes. We found that oncostatin M (OSM), an interleukin-6 family cytokine, in combination with glucocorticoid, induced maturation of hepatocytes as evidenced by morphological changes that closely resemble more differentiated hepatocytes, expression of hepatic differentiation markers and intracellular glycogen accumulation. Consistent with these in vitro observations, livers from mice deficient for gp130, an OSM receptor subunit, display defects in maturation of hepatocytes. Interestingly, OSM is expressed in CD45(+) hematopoietic cells in the developing liver, whereas the OSM receptor is expressed predominantly in hepatocytes. These results suggest a paracrine mechanism of hepatogenesis; blood cells, transiently expanding in the fetal liver, produce OSM to promote development of hepatocytes in vivo.

Animals↗

PubMed1999

Role of cytokine signaling molecules in erythroid differentiation of mouse fetal liver hematopoietic cells: functional analysis of signaling molecules by retrovirus-mediated expression.

Erythropoietin (EPO) and its cell surface receptor (EPOR) play a central role in proliferation, differentiation, and survival of erythroid progenitors. Signals induced by EPO have been studied extensively by using erythroid as well as nonerythroid cell lines, and various controversial results have been reported as to the role of signaling molecules in erythroid differentiation. Here we describe a novel approach to analyze the EPO signaling by using primary mouse fetal liver hematopoietic cells to avoid possible artifacts due to established cell lines. Our strategy is based on high-titer retrovirus vectors with a bicistronic expression system consisting of an internal ribosome entry site (IRES) and green fluorescent protein (GFP). By placing the cDNA for a signaling molecule in front of IRES-GFP, virus-infected cells can be viably sorted by fluorescence-activated cell sorter, and the effect of expression of the signaling molecule can be assessed. By using this system, expression of cell-survival genes such as Bcl-2 and Bcl-XL was found to enhance erythroid colony formation from colony-forming unit-erythroid (CFU-E) in response to EPO. However, their expression was not sufficient for erythroid colony formation from CFU-E alone, indicating that EPO induces signals for erythroid differentiation. To examine the role of EPOR tyrosine residues in erythroid differentiation, we introduced a chimeric EGFR-EPOR receptor, which has the extracellular domain of the EGF receptor and the intracellular domain of the EPOR, as well as a mutant EGFR-EPOR in which all the cytoplasmic tyrosine residues are replaced with phenylalanine, and found that tyrosine residues of EPOR are essential for erythroid colony formation from CFU-E. We further analyzed the function of the downstream signaling molecules by expressing modified signaling molecules and found that both JAK2/STAT5 and Ras, two major signaling pathways activated by EPOR, are involved in full erythroid differentiation.

Animals↗

PubMed1999

Reconstitution of the functional mouse oncostatin M (OSM) receptor: molecular cloning of the mouse OSM receptor beta subunit.

Oncostatin M (OSM) is a member of the interleukin-6 (IL-6) family of cytokines that share the gp130 receptor subunit. Of these family members, leukemia inhibitory factor (LIF) is most closely related to OSM, and various overlapping biologic activities have been described between human LIF and OSM (hLIF and hOSM). Two types of functional hOSM receptors are known: the type I OSM receptor is identical to the LIF receptor that consists of gp130 and the LIF receptor beta subunit (LIFRbeta), and the type II OSM receptor consists of gp130 and the OSM receptor beta subunit (OSMRbeta). It is thus conceivable that common biologic activities between hLIF and hOSM are mediated by the shared type I receptor and OSM-specific activities are mediated by the type II receptor. However, in contrast to the human receptors, recent studies have demonstrated that mouse OSM (mOSM) does not activate the type I receptor and exhibits unique biologic activity. To elucidate the molecular structure of the functional mOSM receptor, we cloned a cDNA encoding mOSMRbeta, which is 55.5% identical to the hOSMRbeta at the amino acid level. mOSM-responsive cell lines express high-affinity mOSM receptors, as well as mOSMRbeta, whereas embryonic stem cells, which are responsive to LIF but not to mOSM, do not express mOSMRbeta. mOSMRbeta alone binds mOSM with low affinity (kd = 13.0 nmol/L) and forms a high-affinity receptor (kd = 606 pmol/L) with gp130. Ba/F3 transfectants expressing both mOSMRbeta and gp130 proliferated in response to mOSM, but failed to respond to LIF and human OSM. Thus, the cloned mOSMRbeta constitutes an essential and species-specific receptor component of the functional mOSM receptor. Reminiscent of the colocalization of the mOSM and mLIF genes, the mOSMRbeta gene was found to be located in the vicinity of the LIFRbeta locus in the proximal end of chromosome 15.

Amino Acid Sequence↗

PubMed1999

Definitive but not primitive hematopoiesis is impaired in jumonji mutant mice.

A novel gene, jumonji was identified by a mouse gene trap strategy. The jumonji gene encodes a protein containing a putative DNA binding domain. The mice homozygous for jumonji gene with a BALB/cA genetic background show hypoplasia of the fetal liver and embryonic lethality, suggesting impaired hematopoiesis. In the peripheral blood of jumonji mutant embryos, the number of fetal liver-derived definitive erythrocytes, but not yolk sac-derived primitive erythrocytes, showed a marked reduction, suggesting that jumonji mutants die of anemia. The defects of definitive erythrocytes in jumonji mutants seemed to be caused by a decrease in the numbers of multiple hematopoietic progenitors including colony-forming unit-spleen (CFU-S) in the fetal liver. However, hematopoietic stem cells (HSCs) in the fetal liver of jumonji mutants could reconstitute the hematopoietic system of lethally irradiated recipients. In the fetal liver, the jumonji gene is expressed in fibroblastic cells and endothelial cells, but not in Lin-/c-Kit+/Sca-1(+) cells known to include HSCs. These results suggest that an environmental defect induce the impaired hematopoiesis in the fetal liver of jumonji mutant embryos.

Animals↗

PubMed1999

Production of radioactive endovascular stents by implantation of 133Xe ions.

A coronary stent was made radioactive by implantation of 133Xe ions for the purpose of suppressing the renarrowing of the part of blood vessel in which the stent is implanted. Electrons of relatively low energies emitted in the decay of 133Xe may give an antiproliferative effect of ionizing radiation to the intimal cells within a limited range of 1 mm. A 133Xe+ beam accelerated at 40 or 60 keV was directed to several stainless steel stents mounted on a target-holder table that could revolve and move up and down to distribute the 133Xe+ ions within a stent as well as among the stents. The radioactive stents produced contained up to 100 kBq of 133Xe and were implanted into the abdominal aortas of rabbits. Neointimal thickening was analyzed by histomorphometry for samples taken 4 weeks after stent implantation. The results indicate that the radioactive stents have a potential to suppress neointimal hyperplasia in rabbits.

Angioplasty, Balloon, Coronary↗

PubMed1999

Identification of podocalyxin-like protein 1 as a novel cell surface marker for hemangioblasts in the murine aorta-gonad-mesonephros region.

Recent studies with avian embryos and murine embryonic stem cells have suggested that hematopoietic cells are derived from hemangioblasts, the common precursors of hematopoietic and endothelial cells. We molecularly cloned podocalyxin-like protein 1 (PCLP1) as a novel surface marker for endothelial-like cells in the aorta-gonad-mesonephros (AGM) region of mouse embryos, where long-term repopulating hematopoietic stem cells (LTR-HSCs) are known to arise. PCLP1+ CD45 cells in the AGM region incorporated acetylated low-density lipoprotein and produced both hematopoietic and endothelial cells when cocultured with OP9 stromal cells. Moreover, multiple lineages of hematopoietic cells were generated in vivo when PCLP1 +CD45-cells were injected into neonatal liver of busulfan-treated mice. Thus, PCLP1 can be used to separate hemangioblasts that give rise to LTR-HSCs.

Amino Acid Sequence↗

PubMed1999

The value of gamma-seminoprotein in combination with prostate specific antigen in detecting prostate cancer.

BACKGROUND: The present study was undertaken to investigate the value of gamma-seminoprotein (gamma-Sm) and the gamma-Sm/prostate specific antigen (PSA) ratio in combination with serum PSA in detecting prostate cancer. METHODS: Prostate specific antigen, gamma-Sm and the gamma-Sm/PSA ratio were evaluated in 112 patients with untreated prostate cancer and 90 patients without prostate cancer who had serum PSA and gamma-Sm levels above their respective detection limits. RESULTS: When data for all of the patients were analyzed, serum PSA and gamma-Sm levels were significantly higher and the gamma-Sm/PSA ratio was significantly lower in patients with prostate cancer than patients without prostate cancer. The serum PSA and gamma-Sm levels significantly increased and the gamma-Sm/PSA ratio significantly decreased with advancing clinical stage in patients with prostate cancer. Among the patients with serum PSA levels ranging from 1.8 to 6 ng/mL, the gamma-Sm/PSA ratio was significantly lower (P < 0.05) and gamma-Sm levels were lower (P = 0.054) in the patients with prostate cancer than in those without prostate cancer, but serum PSA levels were not significantly different (P = 0.53). A receiver operating characteristic (ROC) analysis demonstrated that the areas under the ROC curves were 0.54 for PSA, 0.65 for gamma-Sm and 0.69 for the gamma-Sm/PSA ratio for prediction of prostate cancer in the PSA range from 1.8 to 6 ng/mL, although the ROC analysis suggested that the gamma-Sm/PSA ratio does not provide significant advantage over PSA in detecting prostate cancer when all of the patients were analyzed. CONCLUSIONS: These results suggest that the gamma-Sm/PSA ratio and gamma-Sm may facilitate differentiation between patients with and without prostate cancer who have intermediate PSA levels.

Adenocarcinoma↗

PubMed1999

Integrin-mediated adhesion of endothelial cells induces JAK2 and STAT5A activation: role in the control of c-fos gene expression.

Integrin-mediated adhesion induces several signaling pathways leading to regulation of gene transcription, control of cell cycle entry and survival from apoptosis. Here we investigate the involvement of the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway in integrin-mediated signaling. Plating primary human endothelial cells from umbilical cord and the human endothelial cell line ECV304 on matrix proteins or on antibody to beta1- or alphav-integrin subunits induces transient tyrosine phosphorylation of JAK2 and STAT5A. Consistent with a role for the JAK/STAT pathway in regulation of gene transcription, adhesion to matrix proteins leads to the formation of STAT5A-containing complexes with the serum-inducible element of c-fos promoter. Stable expression of a dominant negative form of STAT5A in NIH3T3 cells reduces fibronectin-induced c-fos mRNA expression, indicating the involvement of STAT5A in integrin-mediated c-fos transcription. Thus these data present a new integrin-dependent signaling mechanism involving the JAK/STAT pathway in response to cell-matrix interaction.

3T3 Cells↗

PubMed1999

Sulfating-activity and stability of cDNA-expressed allozymes of human phenol sulfotransferase, ST1A31 ((213)Arg) and ST1A32 ((213)His), both of which exist in Japanese as well as Caucasians.

We recently found single amino acid substitutions ((213)Arg/His and (223)Met/Val) in polymorphic human phenol-sulfating phenol sulfotransferase (SULT: cDNAs encoding ST1A3, P PST or HAST1/2) among Caucasians and African-Americans. In a Japanese population (n = 143), allele frequencies of (213)Arg and (213)His were 83.2 and 16. 8%, respectively, but the (223)Val allele was not found. (213)His homozygosity was reportedly associated with both very low (>7-fold) sulfating activities of p-nitrophenol (at 4 microM) and low thermostability in platelets. Sulfating-activity determinations using recombinant (213)Arg- and (213)His-forms (ST1A3*1 and ST1A3*2, respectively) did not, however, reveal appreciable deficiency in [(35)S]3'-phosphoadenosine 5'-phosphosulfate (PAPS)-dependent sulfation of p-nitrophenol (4 microM) by ST1A3*2 (7.5 vs. 10.2 nmol/min/nmol SULT for ST1A3). Kinetic parameters for p-nitrophenol for p-nitrophenol sulfation supported the slight decrease in sulfating activities at 4 microM (K(m), 0.82 vs. 1.75 microM; V(max), 13.2 vs. 13.1 nmol/min/nmol SULT, respectively, for ST1A3*1 and *2). p-Nitrophenyl sulfate-dependent 2-naphthol sulfation by ST1A3*2 was 69% of that by ST1A3*1 (p<0.05). However, ST1A3*2 was remarkably unstable at 45 and 37 degrees C as compared to ST1A3*1. The lower p-nitrophenol sulfating activity of ST1A3*2 may explain the lower platelet p-nitrophenol sulfation in ST1A3*2 homozygotes. Protein instability and ST1A3 gene regulation may be both involved in the polymorphism of p-nitrophenol sulfation in human tissues.

Arylsulfotransferase↗

PubMed1999

N-acetylcysteine modifies cis-dichlorodiammineplatinum-induced effects in bladder cancer cells.

We previously demonstrated a role of reactive oxygen species (ROS) in cytotoxicity induced by cis-dichlorodiammineplatinum (CDDP) in combination with glutathione (GSH) depletors in bladder cancer cells. However, the relationship between CDDP and ROS is still unclear, although many mechanisms of drug resistance have been well characterized. The present study was undertaken to investigate the effects of N-acetylcysteine (NAC), a GSH precursor, on the CDDP-induced effects in bladder cancer cells (KU1). The cytotoxic effects of CDDP were significantly blunted by NAC (1 mM) in KU1 cells. The IC50 of CDDP only (10.2+/-1.2 microM) is significantly lower than that of CDDP with NAC (IC50: 20.3+/-1.6 microM) in KU1 cells. NAC also significantly increased the intracellular concentration of GSH in KU1 cells (37.2+/-1.6 nmol/10(6) cells), compared to controls (15.9+/-7.6 nmol/10(6) cells). While CDDP produced a significant increase in ROS as measured in terms of dichlorofluorescein (DCF) production in KU1 cells in a time-dependent manner, pretreatment with NAC significantly reduced CDDP-induced intracellular DCF in KU1 cells. Moreover, TdT-mediated dUTP-biotin nick-end labeling (TUNEL) assay showed that CDDP-induced apoptosis (31.1+/-3.8%) was significantly inhibited by pretreatment with NAC in KU1 cells (11.2+/-2.6%). These results demonstrated that NAC scavenges CDDP-induced ROS and inhibits CDDP-induced cytotoxicity, suggesting that ROS mediate the CDDP-induced cytotoxicity in bladder cancer cells.

Acetylcysteine↗

PubMed1999

Two distinct interleukin-3-mediated signal pathways, Ras-NFIL3 (E4BP4) and Bcl-xL, regulate the survival of murine pro-B lymphocytes.

Hematopoietic cells require cytokine-initiated signals for survival as well as proliferation. The pathways that transduce these signals, ensuring timely regulation of cell fate genes, remain largely undefined. The NFIL3 (E4BP4) transcription factor, Bcl-xL, and constitutively active mutants of components in Ras signal transduction pathways have been identified as key regulation proteins affecting murine interleukin-3 (IL-3)-dependent cell survival. Here we show that expression of NFIL3 is regulated by oncogenic Ras mutants through both the Raf-mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways. NFIL3 inhibits apoptosis without affecting Bcl-xL expression. By contrast, Bcl-xL levels are regulated through the membrane proximal portion in the cytoplasmic domain of the receptor (betac chain), which is shared by IL-3 and granulocyte-macrophage colony-stimulating factor. Activation of either pathway alone is insufficient to ensure cell survival, indicating that multiple independent signal transduction pathways mediate the survival of developing B-lymphoid cells.

Animals↗

PubMed1999

[A patient of successful renal transplantation using donor kidney with congenital abnormalities of the inferior vena cava].

At the time of donor nephrectomy, congenital abnormalities of the inferior vena cava was discovered. A 56-year-old woman was worked up preoperatively and no abnormalities were found. Abdominal aortography was normal. At the time of operation, the inferior vena cava was located to the left and anterior to the abdominal aorta. In the renal hilus, the location of the renal artery and vein was reversal. We thought the ideas of operation and could successfully performed renal transplantation using donor kidney with congenital abnormalities of the inferior vena cava.

Female↗

PubMed1999

Cytokine signaling for proliferation, survival, and death in hematopoietic cells.

The survival, proliferation, and differentiation of hematopoietic cells are regulated by cytokines. In the absence of cytokines, hematopoietic cells not only stop proliferation, but undergo apoptosis. This strict dependency of hematopoietic cells on cytokines is an important mechanism that maintains the homeostasis of blood cells. Cytokines induce various intracellular signaling pathways by activating the receptor-associated Janus kinases (Jaks), and distinct signals are responsible for cell cycle progression and cell survival. Induction of signals for cell cycle progression without suppressing apoptosis results in apoptotic cell death, indicating the essential role of anti-apoptotic signaling for cell growth. In hematopoietic cells, Ras, a cellular protooncogen product, and phosphatidylinositol 3 kinase are involved in the suppression of apoptosis. Cytokine depletion not only turns off anti-apoptotic signaling, but also actively induces cell death by activating caspases, a distinct family of cysteine proteases. Alterations in the mechanisms of cytokine signaling for cell cycle progression and anti-apoptotic function are implicated in hematological disorders.

Apoptosis↗

PubMed1999

[Usefulness of 18F-FDG PET for diagnosis of cardiac sarcoidosis].

Cardiac sarcoidosis, the main cause of death among patients with sarcoidosis, frequently becomes clinically apparent when the disease is far advanced. To evaluate the usefulness of the 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in detecting cardiac sarcoidosis, 18F-FDG PET was performed in 16 patients with sarcoidosis (13 female, 63 +/- 12 yrs), compared with scintigraphic findings of 99mTc-MIBI and 67Ga. Ten of 16 patients were considered to have cardiac complications on clinical grounds with tissue confirmation such as positive endomyocardial biopsy, severe ventricular arrhythmia, more than second degree atrioventricular block, and echocardiographically proven ventricular dysfunction. Among these patients with cardiac complications, abnormal myocardial uptake of FDG were observed in all (100%), which confirms significantly higher frequency compared to 67Ga scintigraphy (50%) (abnormality of 99mTc-MIBI SPECT were observed in 80%). Although abnormal FDG accumulations were observed in region with decreased uptake of 99mTc-MIBI in many cases, localization of regional abnormality of each tracer was frequently independent. This discrepancy may reflect inflammatory and degenerative process of myocardium in cardiac sarcoidosis. 18F-FDG PET is thought to be a useful noninvasive method in detecting cardiac involvement of sarcoidosis and may provide a useful information on the activity of the disease.

Adult↗

PubMed1999

An essential role for nuclear factor kappa B in preventing TNF-alpha-induced cell death in prostate cancer cells.

PURPOSE: Although tumor necrosis factor-alpha (TNF-alpha) induces a strong cytotoxic effect on cell growth, many authors have reported that various cancer cells are resistant to TNF-alpha and the basis for this sensitivity or resistance to TNF-alpha remains to be elucidated. Since nuclear factor kappa B (NF-kappaB) activation has recently been reported to inhibit TNF-alpha-induced cell death, we studied whether NF-kappaB also assumes a protective role in TNF-alpha-induced cell death in prostate cancer cells. MATERIALS AND METHODS: We used two human prostate cancer cell lines of DU145 and PC-3. We prepared two different NF-kappaB inhibitors, pyrrolidine dithiocarbamate (PDTC) and NF-kappaB decoy. NF-kappaB DNA binding activity was detected by electrophoretic mobility shift assay (EMSA). Cell survivals were measured by MTT assay. Induction of apoptosis was detected by nuclear staining and measured by fragmented DNA ELISA. RESULTS: EMSA showed that NF-kappaB inhibitors continuously inhibited TNF-alpha-induced NF-kappaB activation. Cell growth was not inhibited by either TNF-alpha (50 ng./ml. or less) or NF-kappaB inhibitors. However, both PCA cells treated with TNF-alpha (20 ng./ml.) plus NF-kappaB inhibitors showed significant growth inhibition compared with controls (p<0.05). Nuclei of PCA cells appeared severely fragmented by this combination therapy. Furthermore, the levels of DNA fragmentation were significantly elevated in PCA cells treated with TNF-alpha (20 ng./ml.) plus NF-kappaB inhibitors compared with controls (p<0.05). CONCLUSIONS: NF-kappaB activation is suggested to produce the resistance of DU145 and PC-3 to TNF-alpha and that the combination of TNF-alpha and NF-kappaB inhibitors could be constituted an effective therapy to TNF-alpha-resistant human prostate cancer cells.

Apoptosis↗