Roles of NF-κB and 26 S Proteasome in Apoptotic Cell Death Induced by Topoisomerase I and II Poisons in Human Nonsmall Cell Lung Carcinoma

Tabata, Masahiro; Tabata, Rika; Grabowski, Dale; Bukowski, Ronald M.; Ganapathi, Mahrukh K.; Ganapathi, Ram

doi:10.1074/jbc.m009831200

Cited by 47 publications

(40 citation statements)

References 20 publications

(6 reference statements)

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“…The potential role of NF-B in such contexts is somewhat unclear. Although in some cases the inhibition of NF-B by proteasome inhibitors was accompanied by sensitization to cell death initiated by TNF-␣, chemotherapeutic agents, or ionizing radiation [6,7,14], other studies did not demonstrate a requirement for loss of NF-B activity [9,13,15]. Taken together, these findings suggest that apoptosis facilitated by proteasome inhibitors may depend on NF-B inhibition only in specific cell types or the methods used to stimulate the death process.…”

Section: Introductionmentioning

confidence: 92%

Protease inhibitors restore radiation‐induced apoptosis to Bcl‐2‐expressing lymphoma cells

Kurland

Meyn

2001

Intl Journal of Cancer

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SUMMARY The proteasome pathway is important for the turnover of many regulatory proteins. This pathway has recently become a target for antitumor agents and several research groups have demonstrated that inhibitors with specificities for the proteasome are potent apoptosis-inducing agents. Many mechanisms by which proteasome inhibitors exert their effects have been suggested, including inhibition of NF-B activity and stabilization of the p53 tumor suppressor protein. We investigated the ability of inhibitors with specificities for the proteasome and for another protein degradation enzyme, calpain, to sensitize a murine B-cell lymphoma with constitutive NF-B1 homodimer activity and high expression of Bcl-2 protein to radiation-induced apoptosis. Protease inhibitors tested were calpain inhibitor I, calpain inhibitor II, calpeptin, MG132, and Lactacystin. All five inhibitors induced apoptosis and sensitized cells to radiation despite the maintenance of Bcl-2 protein levels throughout the course of treatment. An electrophoretic migration shift assay for NF-B1 activity provided evidence that reversal of NF-B activity was not required for induction of cell death; however, p53 levels were elevated for all inhibitors tested. HL-60 cells, devoid of p53, could not be sensitized to radiation by MG132 treatment, suggesting that p53 was important for cell death induced by combined treatment with protease inhibitors and radiation. We concluded that protease inhibitors are capable of overcoming the protective effects of Bcl-2 to induce apoptosis and suggest that protease inhibitor treatment, when combined with ionizing radiation, leads to p53-mediated apoptosis.

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Section: Introductionmentioning

confidence: 92%

Protease inhibitors restore radiation‐induced apoptosis to Bcl‐2‐expressing lymphoma cells

Kurland

Meyn

2001

Intl Journal of Cancer

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“…The human non-small-cell lung carcinoma apoptosis induced by topoisomerase poisons, e.g. Etoposide, is not mediated by NF-κB, but can be manipulated by proteasome inhibitors (Tabata et al, 2001). Why NF-κB plays a role in apoptosis that is induced by some agents and not others is unclear, but suggests that the apoptotic pathway varies from one inducer to another, and also perhaps from one cell type to another.…”

Section: Evidence That Apoptosis Is Unaffected By Nf-kappabmentioning

confidence: 99%

Nuclear Factor-κB Activation: A Question of Life or Death

Shishodia¹,

Aggarwal²

2002

BMB Reports

206

168

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Apoptosis is a mode of cell death that plays an important role in both pathological and physiological processes. Research during the last decade has delineated the entire machinery needed for cell death, and its constituents were found to pre-exist in cells. The apoptotic cascade is triggered when cells are exposed to an apoptotic stimulus. It has been known for several years that inhibitors of protein synthesis can potentiate apoptosis that is induced by cytokines and other inducers. Until 1996, it was not understood why protein synthesis inhibitors potentiate apoptosis. Then three reports appeared that suggested the role of the transcription factor NF-κB activation in protecting the cells from TNF-induced apoptosis. Since then several proteins have been identified that are regulated by NF-κB and are involved in cell survival, proliferation, and protection from apoptosis. It now seems that when a cell is attacked by an apoptotic stimulus, the cell responds first by activating anti-apoptotic mechanisms, which may or may not be followed by apoptosis. Whether or not a cell undergoes proliferation, the survival, or apoptosis, appears to involve a balance between the two mechanisms. Inhibitors of protein synthesis seem to suppress the appearance of protein that are involved in anti-apoptosis. The present review discusses how NF-κB controls apoptosis.

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“…Additionally, compound 9 inhibited the proliferation of two drugresistant leukemia cells to the same extent as parent cells. Topoisomerase I (Topo I) inhibitors are known to induce cancer cell apoptosis, and compound 10 was shown to be a potent inhibitor of eukaryotic Topo I (Tabata et al 2001;Chowdhury et al 2002). Compounds 8-12 with a carbonyl group at C-17 markedly inhibited human Topo I, but compound 1 and compound 5 did not affect on the enzyme activity (Fig.…”

Section: Structure-activity Relationships Of Melanogenesis and Apoptomentioning

confidence: 99%

Differentiation-inducing activity of lupane triterpenes on a mouse melanoma cell line

et al. 2006

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Lupane triterpenes were found to promote melanogenesis, a hallmark of B16 2F2 mouse melanoma cell differentiation. Studies of the structureactivity relationships demonstrated that the keto function at C-3 of the lupane skeleton played important roles in the melanogenic activities of lupane triterpenes on melanoma cells. The carbonyl group at C-17 of lupane triterpenes was essential against their apoptosis-inducing activity against human cancer cells via the inhibition of topoisomerase I. We investigated whether signaling mechanisms were involved in the stimulative effects of lupane triterpenes on the melanogenesis of B16 2F2 cells. In experiments using selective inhibitors against various signal transduction molecules and Western blotting analysis, it was suggested that p38 MAPK was involved in melanoma cell differentiation as a downstream effector of PKA. Lupeol (compound 1), a lupane triterpene, induced dendrite formations, a morphological hallmark of B16 2F2 cell differentiation by rearrangement of the actin cytoskeleton.The activation of cofilin, an actin depolymerizing factor, by compound 1 caused actin fiber disassembly in B16 2F2 cells. Furthermore, compound 1 was shown to inhibit the cell motilities of human melanoma and neuroblastoma in vitro.

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Roles of NF-κB and 26 S Proteasome in Apoptotic Cell Death Induced by Topoisomerase I and II Poisons in Human Nonsmall Cell Lung Carcinoma

Cited by 47 publications

References 20 publications

Protease inhibitors restore radiation‐induced apoptosis to Bcl‐2‐expressing lymphoma cells

Protease inhibitors restore radiation‐induced apoptosis to Bcl‐2‐expressing lymphoma cells

Nuclear Factor-κB Activation: A Question of Life or Death

Differentiation-inducing activity of lupane triterpenes on a mouse melanoma cell line

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