Induction of Apoptosis of Cytokine-Producing Bladder Cancer Cells by Adenovirus-Mediated I kappa B alpha Overexpression

Sumitomo, Makoto; Tachibana, Masaaki; Ozu, Choichiro; Asakura, Hirotaka; Murai, Masaru; Hayakawa, Masamichi; Nakamura, Hiroshi; Takayanagi, Atsushi; Shimizu, Nobuyoshi

doi:10.1089/10430349950019174

Cited by 65 publications

(46 citation statements)

References 34 publications

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“…Importantly, many other tumors have recently been shown to display constitutive activation of NF-kB (reviewed in Rayet and Gelinas, 1999), including the human cutaneous T-cell lymphoma HuT-78 (Giri and Aggarwal, 1998), Hodgkin's lymphomas (Bargou et al, 1997), melanoma (Shattuck et al, 1994) pancreatic adenocarcinoma (Wang et al, 1999), primary adult T-cell leukemia (Mori et al, 1999), and head and neck squamous cell carcinoma (Du ey et al, 1999). Furthermore, the Tax transforming protein produced by the human T-cell leukemia virus type 1 induces NF-kB activity (Mercurio et al, 1997;Sun et al, 1994) through activation of both IKK1 and IKK2 (Geleziunas et al, 1998;Sumitomo et al, 1999b). Moreover, NF-kB induction has been found to inhibit TNF-a-induced cell death of breast, prostate, and bladder cancer cells (Geleziunas et al, 1998;Sumitomo et al, 1999a) (reviewed in Rayet andGelinas, 1999).…”

Section: Discussionmentioning

confidence: 99%

Her-2/neu overexpression induces NF-κB via a PI3-kinase/Akt pathway involving calpain-mediated degradation of IκB-α that can be inhibited by the tumor suppressor PTEN

et al. 2001

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The Nuclear Factor (NF)-kB family of transcription factors controls expression of genes which promote cell growth, survival, and neoplastic transformation. Recently we demonstrated aberrant constitutive activation of NFkB in primary human and rat breast cancer specimens and in cell lines. Overexpression of the epidermal growth factor receptor (EGFR) family member Her-2/neu, seen in approximately 30% of breast cancers, is associated with poor prognosis. Previously, Her-2/neu has been shown to signal via a phosphatidylinositol 3 (PI3)-kinase to Akt/protein kinase B (PKB) pathway. Since this signaling pathway was recently shown to activate NFkB, here we have tested the hypothesis that Her-2/neu can activate NF-kB in breast cancer. Overexpression of Her-2/neu and EGFR-4 in Ba/F3 cells led to constitutive PI3-and Akt kinase activities, and induction of classical NF-kB (p50/p65). Similarly, a tumor cell line and tumors derived from MMTV-Her-2/neu transgenic mice displayed elevated levels of classical NF-kB. Engagement of Her-2/neu receptor downregulated the level of NF-kB. NF-kB binding and activity in the cultured cells was reduced upon inhibition of the PI3-to Akt kinase signaling pathway via ectopic expression of kinase inactive mutants, incubation with wortmannin, or expression of the tumor suppressor phosphatase PTEN. Inhibitors of calpain, but not the proteasome, blocked IkB-a degradation. Inhibition of Akt did not a ect IKK activity. These results indicate that Her-2/neu activates NF-kB via a PI3-to Akt kinase signaling pathway that can be inhibited via the tumor suppressor PTEN, and is mediated by calpain rather than the IkB kinase complex.

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Section: Discussionmentioning

confidence: 99%

Her-2/neu overexpression induces NF-κB via a PI3-kinase/Akt pathway involving calpain-mediated degradation of IκB-α that can be inhibited by the tumor suppressor PTEN

et al. 2001

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“…An anti-apoptotic role of NF-B has been linked to T cell lymphoma, osteoclasts, 134 melanoma, 135 pancreatic cancer, 136 bladder cancer, 137 and breast cancer. 138 Cell types (not necessarily oncogenes) that display an anti-apoptotic role for NF-B include B cells, 139,140 T cells 141,142 granulocytes, 143 macrophages, 144 neuronal cells, 145,146 and smooth muscle cells.…”

Section: Nf-b In Apoptosis Cell Proliferation and Tumor Initiationmentioning

confidence: 99%

Nuclear transcription factor-κB as a target for cancer drug development

2002

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Nuclear factor kappa B (NF-B) is a family of inducible transcription factors found virtually ubiquitously in all cells. Since its discovery by Sen and Baltimore in 1986, much has been discovered about its mechanisms of activation, its target genes, and its function in a variety of human diseases including those related to inflammation, asthma, atherosclerosis, AIDS, septic shock, arthritis, and cancer. Due to its role in a wide variety of diseases, NF-B has become one of the major targets for drug development. Here, we review our current knowledge of NF-B, the possible mechanisms of its activation, its potential role in cancer, and various strategies being employed to target the NF-B signaling pathway for cancer drug development.

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“…21,22 This I B⌬N lacks the 54 NH 2 -terminal amino acids present in wild-type human I B␣ (MAD3). It has been reported to be neither phosphorylated nor proteolyzed in response to signal induction but to fully inhibit NF-B.…”

Section: Recombinant Adenovirus Vectorsmentioning

confidence: 99%

Overexpression of Truncated IκBα Induces TNF-α–Dependent Apoptosis in Human Vascular Smooth Muscle Cells

Obara

Takayanagi

Hirahashi

et al. 2000

ATVB

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Abstract-Dysregulation of apoptosis is one of the likely underlying mechanisms of neointimal thickening, a disorder in which proinflammatory cytokines may influence the function of vascular smooth muscle cells (VSMCs) and contribute to atherogenesis. One of these cytokines, tumor necrosis factor-␣ (TNF-␣), induces 2 possibly conflicting pathways, 1 leading to the activation of nuclear factor-B (NF-B) and the other leading to caspase-mediated apoptosis. We investigated whether specific inhibition of NF-B affects TNF-␣-dependent apoptosis in human VSMCs. To inhibit NF-B activation specifically, we constructed a recombinant adenovirus vector expressing a truncated form of the inhibitor protein I B␣ (AdexI B⌬N) that lacks the phosphorylation sites essential for activation of NF-B. The I B⌬N was overexpressed by adenoviral infection and was resistant to stimulus-dependent degradation. Electromobility gel shift and luciferase assays demonstrated that overexpression of I B⌬N inhibited NF-B activation induced by TNF-␣ or interleukin-1␤ (IL-1␤). In cells overexpressing I B⌬N, TNF-␣ dramatically induced apoptosis, whereas IL-1␤ had no effect. The induction was suppressed by treatment with a selective inhibitor of the caspase-3 family, Z-DEVD-fmk, and the overexpression of I B⌬N induced TNF-␣-mediated caspase-3 and caspase-2 activity. These results indicate that overexpression of I B⌬N induces TNF-␣-dependent apoptosis by efficient and specific suppression of NF-B and upregulation of caspase-3 and caspase-2 activity in human VSMCs. Our findings suggest that adenovirus-mediated I B⌬N gene transfer may be useful in the treatment of disorders associated with inflammatory conditions, such as the response to vascular injury and atherosclerosis. (Arterioscler Thromb Vasc

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Induction of Apoptosis of Cytokine-Producing Bladder Cancer Cells by Adenovirus-Mediated I kappa B alpha Overexpression

Cited by 65 publications

References 34 publications

Her-2/neu overexpression induces NF-κB via a PI3-kinase/Akt pathway involving calpain-mediated degradation of IκB-α that can be inhibited by the tumor suppressor PTEN

Her-2/neu overexpression induces NF-κB via a PI3-kinase/Akt pathway involving calpain-mediated degradation of IκB-α that can be inhibited by the tumor suppressor PTEN

Nuclear transcription factor-κB as a target for cancer drug development

Overexpression of Truncated IκBα Induces TNF-α–Dependent Apoptosis in Human Vascular Smooth Muscle Cells

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