Administration of IκB-kinase inhibitor PS 1145 enhances apoptosis in DMBA induced tumor in male Wistar rats (original) (raw)
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Oncogene, 2005
A key antiapoptotic transcription factor, nuclear factor kappa-B (NF-jB), is known to be critically important for tumor cell growth, angiogenesis and development of metastatic lesions. We and others showed previously that NF-jB transcription factor was constitutively activated in androgen-independent prostate carcinoma (PC) cell lines due to the upregulated activity of inhibitor of NF-jB kinases (IKK). In this work, using luciferase assay, electrophoretic mobility shift assay and Northern blot analysis of expression of endogenous jB-responsive genes, we demonstrate that a novel highly specific small-molecule IKK inhibitor, PS1145, efficiently inhibited both basal and induced NF-jB activity in PC cells. We found that PS1145 induced caspase 3/7-dependent apoptosis in PC cells and significantly sensitized PC cells to apoptosis induced by tumor necrosis factor alpha. We also showed that PS1145 inhibited PC cell proliferation. Effects of PS1145 on proliferation and apoptosis correlated with inhibition of interleukin (IL)-6, cyclin D1, D2, inhibitor of apoptosis (IAP)-1 and IAP-2 gene expression and decreased IL-6 protein level. In addition, we found that incubation with PS1145 inhibited the invasion activity of highly invasive PC3-S cells in invasion chamber assay in a dose-dependent manner. Overall, this study provides the framework for development of a novel therapeutic approach targeting NF-jB transcription factor to treat advanced PC.
Clinical Cancer Research, 2001
We have shown that activation of nuclear factor-B (NF-B) promotes cell survival and expression of cytokines such as growth-regulated oncogene-␣, which can modulate angiogenesis, growth, and metastasis of squamous cell carcinoma (SCC). Activation of NF-B and cytoprotective genes in cancer may result from signal-induced phosphorylation and proteasome-dependent degradation of inhibitor-B. In this study, we examined the effects of the novel proteasome inhibitor PS-341 on activation of NF-B and cell survival, growth, and angiogenesis in murine and human SCC cell lines. PS-341 inhibited activation of NF-B DNA binding and functional reporter activity at concentrations between 10 ؊8 and 10 ؊7 M. Cytotoxicity was observed at 10 ؊7 M in four murine and two human SCC lines, and followed early cleavage of poly(ADP-ribose) polymerase, a marker of caspase-mediated apoptosis. In vivo, PS-341 inhibited growth of murine and human SCC in mice at doses of 1-2 mg/kg given three times weekly, and dose-limiting toxicity was encountered at 2 mg/kg. Tumor growth inhibition was associated with a marked decrease in vessel density. PS-341 inhibited expression of the proangiogenic cytokines growthregulated oncogene-␣ and vascular endothelial growth factor by SCC in the range at which PS-341 inhibits NF-B. We conclude that PS-341 inhibits activation of NF-B pathway components related to cell survival, tumor growth, and angiogenesis in SCC.
Regulation of NF-κB activity by IκB-related proteins in adenocarcinoma cells
Oncogene, 1999
Constitutive NF-kB activity varies widely among cancer cell lines. In this report, we studied the expression and the role of dierent IkB inhibitors in adenocarcinoma cell lines. High constitutive NF-kB activity and low IkBa expression was found in a number of these cell lines. Moreover, some of these cells showed a high p100 expression, responsible for the cytoplasmic sequestration of most of p65 complexes. Treatment of these cells with TNF-a or other NF-kB activating agents induced only weakly nuclear NF-kB activity without signi®cant p100 processing and led to a very weak transcription of NF-kB-dependent reporter gene. Induction of NF-kB activity can be restored by expression of the Tax protein or by treatment with antisense p100 oligonucleotides. In MCF7 A/Z cells stably transfected with a p100 expression vector, p65 complexes were sequestered in the cytoplasm by p100. These cells showed a reduced nuclear NF-kB induction and NF-kB-dependent gene transcription following TNF-a stimulation. As a consequence of a competition between IkB-a and p100, cells expressing high levels of p100 respond poorly to NF-kB activating stimuli as TNF-a.
Expression of Ki67 in Precancerous Squamous Cell Skin Lesion of Mice Induced by DMBA
Indonesian Journal of Cancer, 2019
Background: Squamous cell carcinoma (SCC) is an invasive skin cancer that is found in the human skin. SCC growth from the precancerous lesion is known as a wart or papilloma. Ki67 is a protein expressed by cells during proliferation. Cells with higher Ki67 expression showed abnormal regulation of apoptosis. 5-FU is an antimetabolite compound that works as a DNA/RNA pyrimidine antagonist molecule that can induce cell apoptosis. The main objective of this research is to evaluate the inhibition proliferation of precancerous squamous cell in skin lesion induced by DMBA/croton oil treated by using 5-FU cream topically compared to 5% imiquimod cream. Methods: This research assesses three different concentrations of 5-FU cream namely 1%, 2%, and 5% topically on 24 wild type mice divided into 6 groups of 4 each including positive control (with carcinogenesis but without treatment), negative control (without treatment ; normal), carcinogenesis with treatment 5-FU cream (1%, 2%, and 5%) or 5%...
NF-kappaB2 p100 is a pro-apoptotic protein with anti-oncogenic function
2002
Nuclear factor-κ κB (NF-κ κB) promotes cell survival by upregulating expression of anti-apoptotic genes, a process that is antagonized by inhibitors of κ κB (Iκ κB) factors 1 . The only NF-κ κB family member known to be mutated in human cancer is NF-κ κB2 p100 (ref. 2), a factor with Iκ κB activity. Here, we report the isolation from irradiated mouse tumour cells of a complex that induces caspase-8 activity in cell-free assays and identify p100 as an essential component of this complex. Expression of p100 profoundly sensitizes cells to death-receptor-mediated apoptosis through a pathway that is independent of Iκ κB-like activity. The carboxyl terminus of p100 contains a death domain 3 that is absent from all known tumour-derived mutants. This death domain mediates recruitment of p100 into death machinery complexes after ligand stimulation and is essential for p100's pro-apoptotic activity. p100 also sensitizes NIH3T3 cells to apoptosis triggered by oncogenic Ras, resulting in a marked inhibition of transformation that is rescued by suppression of endogenous caspase-8. These observations thus identify an Iκ κBindependent apoptotic activity of NF-κ κB2 p100 and help explain its unique tumour suppressor role.
Constitutive activation of IκB kinase α and NF-κB in prostate cancer cells is inhibited by ibuprofen
Oncogene, 1999
Apoptotic pathways controlled by the Rel/NF-kB family of transcription factors may regulate the response of cells to DNA damage. Here, we have examined the NF-kB status of several prostate tumor cell lines. In the androgen-independent prostate tumor cells PC-3 and DU-145, the DNA-binding activity of NF-kB was constitutively activated and IkB-a levels were decreased. In contrast, the androgen-sensitive prostate tumor cell line LNCaP had low levels of NF-kB which were upregulated following exposure to cytokines or DNA damage. The activity of the IkB-a kinase, IKKa, which mediates NF-kB activation, was also measured. In PC-3 cells, IKKa activity was constitutively active, whereas LNCaP cells had minimal IKKa activity that was activated by cytokines. The anti-in¯ammatory agent ibuprofen inhibited the constitutive activation of NF-kB and IKKa in PC-3 and DU-145 cells, and blocked stimulated activation of NF-kB in LNCaP cells. However, ibuprofen did not directly inhibit IkB-a kinase. The results demonstrate that NF-kB is constitutively activated in the hormone-insensitive prostate tumor cell lines PC-3 and DU-145, but not in the hormone responsive LNCaP cell line. The constitutive activation of NF-kB in prostate tumor cells may increase expression of anti-apoptotic proteins, thereby decreasing the eectiveness of anti-tumor therapy and contributing to the development of the malignant phenotype.
Clinical Cancer Research, 2005
Purpose: Defective apoptosis signaling is a typical feature of classic Hodgkin's lymphoma, multiple myeloma, and activated B-cell-like diffuse large B-cell lymphoma. In these malignancies, the transcription factor nuclear factor-κB (NF-κB) is a critical mediator of apoptosis resistance and oncogenic growth, making it an attractive therapeutic target. Here, we sought to determine how to overcome apoptosis resistance experimentally in these malignancies by targeting NF-κB.Experimental Design: We investigated the effect of different inhibitors of NF-κB on classic Hodgkin's lymphoma, multiple myeloma, and activated B-cell-like diffuse large B-cell lymphoma cell lines harboring different molecular defects in apoptosis signaling both quantitatively and qualitatively.Results: The cyclopentenone prostaglandin, 15-deoxy-Δ12,14-prostaglandin J2, a known inhibitor of NF-κB, induced caspase-dependent apoptosis; it restored mitochondrial apoptotic signaling by down-regulation of X-linked...
High constitutive level of NF-κB is crucial for viability of adenocarcinoma cells
Cell Death and Differentiation, 2001
Most of cells exhibit low nuclear level of NF-kB. However, in some cell lines and tissues aberrantly activated NF-kB is playing an important role in cell motility, growth control and survival. Here we describe the result of decrease of constitutive NF-kB level in different adenocarcinoma cell lines. Treatment of mouse adenocarcinoma cell line CSML-100 with both synthetic (TPCK or PDTC) or natural (IkB-a) NF-kB inhibitors caused apoptotic death. Low doses of TPCK were harmless for CSML100 cells but sensitized them to TNFinduced apoptosis. Death of CSML100 cells in the presence of high concentration TPCK was not accompanied with significant changes in c-myc activity but strongly correlated with rapid decrease in p53 level. Thus, mutual behavior p53 and NF-kB represented a unique feature of TPCK-induced apoptosis in CSML-100 adenocarcinoma cells. Cell Death and Differentiation (2001) 8, 621 ± 630.