Loss of IKKβ activity increases p53 stability and p21 expression leading to cell cycle arrest and apoptosis

Yang, Pei Ming; Huang, Wei; Lin, Yen-Ko; Huang, Wenyu; Wu, Hui; Chen, Wei Lun; Chang, Yu Fan; Chou, Chih‐Ju; Tzeng, Cherng Chyi; Chen, Yeh Long; Chen, Ching-Chow

doi:10.1111/j.1582-4934.2009.00712.x

Cited by 21 publications

(21 citation statements)

References 57 publications

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“…In view of the above, we assumed that the SASH1 gene possibly blocked cyclin B1-Cdc2 binding, either directly or indirectly, leading to G2/M arrest. Although p53 can affect cyclin B1/Cdc2 activity, resulting in G2/M arrest (26)(27)(28), no statistically significant difference was observed in the TP53 mRNA level between the A-375 (SASH1) and A-375 (EGFP) cells. Therefore, it did not account for the G2/M arrest.…”

Section: Discussionmentioning

confidence: 99%

Effects of SASH1 on melanoma cell proliferation and apoptosis in vitro

Lin

Zhang

et al. 2012

Molecular Medicine Reports

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Abstract. The SAM and SH3 domain containing 1 (SASH1) gene was originally identified as a potential tumor suppressor gene in breast cancer, mapped on chromosome 6q24.3. The expression of SASH1 plays a prognostic role in human colon cancer. Its expression is frequently downregulated in several human malignancies. However, the biological function of SASH1 in melanoma cells is yet to be determined. In this study, in order to investigate the tumor suppressive effects of the SASH1 gene, an A-375 stable melanoma cell line was established, overexpressing the SASH1 gene. The stable cell line was examined using proliferation assay, apoptosis assay, cell cycle analysis and real-time PCR. The results indicated that the tumor suppressive activity of SASH1 derived from G2/M arrest in A-375 cells, and that the phosphorylation of Cdc2 or the disruption of cyclin B-Cdc2 binding may be responsible for the G2/M arrest.

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Section: Discussionmentioning

confidence: 99%

Effects of SASH1 on melanoma cell proliferation and apoptosis in vitro

Lin

Zhang

et al. 2012

Molecular Medicine Reports

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“…A close and complex relationship is evident between tumor cell apoptosis and cell cycle arrest [21] . Although apoptosis and cell cycle arrest complement each other by inhibiting tumor progression, the effects of CrTX on tumor cell apoptosis and G 1 arrest are achieved via distinct intracellular pathways.…”

Section: Discussionmentioning

confidence: 99%

Anti-tumor activity of CrTX in human lung adenocarcinoma cell line A549

et al. 2011

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Aim: To assess the cytotoxic effect of crotoxin (CrTX), a potent neurotoxin extracted from the venom of the pit viper Crotalus durissus terrificus, in human lung adenocarcinoma A549 cells and investigated the underlying mechanisms. Methods: A549 cells were treated with gradient concentrations of CrTX, and the cell cycle and apoptosis were analyzed using a flow cytometric assay. The changes of cellular effectors p53, caspase-3 and cleaved caspase-3, total P38MAPK and pP38MAPK were investigated using Western blot assays. A549 xenograft model was used to examine the inhibition of CrTX on tumor growth in vivo. Results: Treatment of A549 cells with CrTX (25-200 μg/mL) for 48 h significantly inhibited the cell growth in a dose-dependent manner (IC 50 =78 μg/mL). Treatment with CrTX (25 μg/mL) for 24 h caused G1 arrest and induced cell apoptosis. CrTX (25 μg/mL) significantly increased the expression of wt p53, cleaved caspase-3 and phospho-P38MAPK. Pretreatment with the specific P38MAPK inhibitor SB203580 (5 μmol/L) significantly reduced CrTX-induced apoptosis and cleaved caspase-3 level, but G 1 arrest remained unchanged and highly expressed p53 sustained. Intraperitoneal injection of CrTX (10 μg/kg, twice a week for 4 weeks) significantly inhibited A549 tumor xenograft growth, and decreased MVD and VEGF levels. Conclusion: CrTX produced significant anti-tumor effects by inducing cell apoptosis probably due to activation of P38MAPK and caspase-3, and by cell cycle arrest mediated by increased wt p53 expression. In addition, CrTX displayed anti-angiogenic effects in vivo.

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“…Distinct suppression mechanisms of p53 functions by NF-κB have been reported. 30) The response of p53 to DNA damage was inhibited by NF-κB; through inducing the expression of E3 ubiquitin ligase Hdm2 (Mdm2 in mice) that destabilizes p53. 30) Importantly, the following corroborative associations have been reported of (a) cyclin D1 over-expression (or low expression of CDKIp27) with poor survival among CCA patients 6,7,9) and (b) p53 inactivation or NF-κB activation with the development of CCA.…”

Section: Discussionmentioning

confidence: 99%

“…29,53) An association between the down-modulation of NF-κB activity in the cytosol and the nucleus with an apoptotic response of the eukaryotic cells has been reported. 30) Recent research shows that gambogic acid suppresses the NF-κB activation by various inflammatory agents and carcinogens. 21) Gambogic acid inhibited tumor necrosis factor (TNF)-induced NF-κB activation through inhibition of IKK activation leading to suppression of NF-κB/p65 phosphorylation and translocation of NF-κB/p65 into the nucleus resulting the increase of cytosol IκB-α protein level.…”

Section: Discussionmentioning

confidence: 99%

“…28,29) Since the down-modulation of NF-κB activity in the cytosol and nucleus is associated with an apoptotic response among eukaryotic cells, 30) the effect of isomorellin on the protein expression of NF-κB/p65 in both CCA cell lines was examined. Using Western blotting analysis, isomorellin treatment of KKU-100 (0-8 µM) and KKU-M156 (0-4 µM) cell lines for 24 h was found to significantly reduce the protein expression of NF-κB/p65 in whole cell, cytosol and nuclear lysates in a dose-dependent manner in both CCA cell lines over against the control cells (Fig.…”

Section: Inhibition Of Nf-κb Activation In Cca Cell Lines Bymentioning

confidence: 99%

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Involvement of p53 and Nuclear Factor-kappaB Signaling Pathway for the Induction of G1-Phase Cell Cycle Arrest of Cholangiocarcinoma Cell Lines by Isomorellin

Hahnvajanawong

Ketnimit

Pattanapanyasat

et al. 2012

Biological & Pharmaceutical Bulletin

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Cell cycle arrest is closely linked to apoptosis. Isomorellin-a caged xanthone isolated from Garcinia hanburyi-induced apoptosis in cholangiocarcinoma (CCA) cell lines. To elucidate potential anticancer mechanisms, we investigated the effects of isomorellin on the growth, cell cycle progression, cell cycle regulated protein expression and nuclear factor-kappa B (NF-κB) activation of KKU-100 and KKU-M156 CCA cell lines; using sulforhodamine B assay, flow cytometry and Western blot analysis. The growth of both CCA cell lines was significantly inhibited by isomorellin treatment in a time-and dose-dependent manner. The respective IC 50 value of isomorellin for KKU-100 cells was 6.2 0.13, 5.1 0.11 and 3.5 0.25 µM at 24, 48 and 72 h. By comparison, the respective IC 50 value for KKU-M156 cells was 1.9 0.22, 1.7 0.14 and 1.5 0.14 µM at 24, 48 and 72 h. The growth inhibition of CCA cells by isomorellin was through the G0/G1 phase arrest mediated by inhibition of NF-κB activation, up-regulation of p53, p21 and p27 and down-regulation of cyclin D1, cyclin E, Cdk4 and Cdk2 protein levels. Our research suggests that isomorellin induces cell cycle arrest and apoptosis in CCA cell lines through p53 and the NF-κB-signaling pathway. The growth inhibitory potential of isomorellin was comparable to that of gambogic acid. Isomorellin shows potential as a therapeutic agent against human cholangiocarcinoma.

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Loss of IKKβ activity increases p53 stability and p21 expression leading to cell cycle arrest and apoptosis

Cited by 21 publications

References 57 publications

Effects of SASH1 on melanoma cell proliferation and apoptosis in vitro

Effects of SASH1 on melanoma cell proliferation and apoptosis in vitro

Anti-tumor activity of CrTX in human lung adenocarcinoma cell line A549

Involvement of p53 and Nuclear Factor-kappaB Signaling Pathway for the Induction of G1-Phase Cell Cycle Arrest of Cholangiocarcinoma Cell Lines by Isomorellin

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