Epidermal growth factor inhibition of c-Myc-mediated apoptosis through Akt and Erk involves Bcl-xL upregulation in mammary epithelial cells

Ramljak, Danica; Coticchia, Christine M.; Nishanian, Tagvor G.; Saji, Motoyasu; Ringel, Matthew D.; Conzen, Suzanne D.; Dickson, Robert B.

doi:10.1016/s0014-4827(03)00135-6

Cited by 34 publications

(28 citation statements)

References 44 publications

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“…Studies through activation of the mitogen-activated protein kinase (MAPK) and PI3K/AKT pathways showed that Snailexpressing cells show hyperactivation of MAPK and PI3K/AKT activities. Both pathways can modulate the upregulation of Bcl-XL expression (48). We show here that the treatment with Snail siRNA inhibited phospho-AKT.…”

Section: Discussionmentioning

confidence: 58%

Galiximab Signals B-NHL Cells and Inhibits the Activities of NF-κB–Induced YY1- and Snail-Resistant Factors: Mechanism of Sensitization to Apoptosis by Chemoimmunotherapeutic Drugs

Martínez-Paniagua¹,

Vega²,

Huerta-Yépez³

et al. 2012

Molecular Cancer Therapeutics

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Galiximab (anti-CD80 monoclonal antibody) is a primatized (human IgG1 constant regions and cynomologus macaque variable regions) monoclonal antibody that is currently in clinical trials. Galiximab inhibits tumor cell proliferation through possibly cell signaling-mediated effects. Thus, we hypothesized that galiximab may signal the tumor cells and modify intracellular survival/antiapoptotic pathways such as the NF-kB pathway. This hypothesis was tested using various CD80þ Burkitt B-NHL (non-Hodgkin lymphomas)cell lines as models. Treatment of B-NHL cells with galiximab (25-100 mg/mL) resulted in significant inhibition of NF-kB activity and its target resistant factors such as YY1, Snail, and Bcl-2/Bcl-XL. Treatment of B-NHL cells with galiximab sensitized the tumor cells to both cis-diamminedichloroplatinum(II) (CDDP)-and TRAILinduced apoptosis. The important roles of YY1-and Snail-induced inhibition by galiximab in the sensitization to CCDP and TRAIL were corroborated following transfection of Raji cells with YY1 or Snail short interfering RNA. The transfected cells were shown to become sensitive to both CCDP-and TRAIL-induced apoptosis in the absence of galiximab. Furthermore, knockdown of YY1 or Snail inhibited Bcl-XL. The involvement of Bcl-XL inhibition in sensitization was corroborated by the use of the pan-Bcl-2 inhibitor 2MAM-3 whereby the treated cells were sensitive to both CDDP-and TRAIL-induced apoptosis. These findings show that galiximab inhibits the NF-kB/Snail/YY1/Bcl-XL circuit that regulates drug resistance in B-NHL and in combination with cytotoxic drugs results in apoptosis. The findings also support the therapeutic application of the combination of galiximab and cytotoxic drugs in the treatment of drug-resistant CD80-positive B-cell malignancies.

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Section: Discussionmentioning

confidence: 58%

Galiximab Signals B-NHL Cells and Inhibits the Activities of NF-κB–Induced YY1- and Snail-Resistant Factors: Mechanism of Sensitization to Apoptosis by Chemoimmunotherapeutic Drugs

Martínez-Paniagua¹,

Vega²,

Huerta-Yépez³

et al. 2012

Molecular Cancer Therapeutics

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“…31 One mechanism how activated p42/44 MAP kinases (extracellular signal-regulated kinase 1/2 (ERK1/2)) suppress apoptosis is by upregulating Bcl-x L , [32][33][34] and in mammary epithelial cells a significant decrease in Bcl-x L protein has been reported by using pharmacological inhibitors of both the PI3K/Akt and the p42/44 MAPK pathways. 35 We used a specific inhibitor of the activation of mitogen-activated protein kinase kinase (MAPKK), PD 98,059, 36 to investigate the role of p42/44 MAP kinases in muristerone A-induced inhibition of RKO cell apoptosis. Figure 3e shows that inhibition of the p42/p44 MAPK pathway by PD 98,059 once again reintroduces FasL sensitivity in muristerone A-treated cells.…”

Section: Resultsmentioning

confidence: 99%

Agonists of an ecdysone-inducible mammalian expression system inhibit Fas Ligand- and TRAIL-induced apoptosis in the human colon carcinoma cell line RKO

2005

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The ecdysone-inducible mammalian expression system is frequently used for inducible transgene expression in vitro and in vivo. Here, we describe a strong antiapoptotic effect of ecdysone analogs in the human colon carcinoma cell line RKO, which is in contrast to published data that ecdysteroids do not influence mammalian cell physiology. Inhibition of Fas ligand-and TNF-related apoptosis-inducing ligand-induced apoptosis by muristerone A occurs at the level of caspase-8 activation and is neutralized by phosphatidylinositol-3-kinase/Akt, protein kinase C and mitogen-activated protein kinase inhibitors. Microarray, Northern and Western blot analysis revealed that incubation of RKO cells with muristerone A leads to changes in gene expression levels, including an upregulation of bcl-x L mRNA and protein levels. Our data imply that ecdysteroids and ecdysone mimics can induce and/or repress gene transcription in RKO and other mammalian cells, thereby influencing the apoptotic behavior. Therefore, the ecdysone-inducible mammalian expression system may not be suitable for the analysis of apoptosisrelated genes.

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“…Furthermore, Erk activation can provide survival signals through inhibitory phosphorylation of caspase 9 (1) as well as through activating phosphorylation of IEX-1 (20), either of which may play a role in G 1 /S-mediated anoikis resistance. Sustained Erk activation in G 1 /S-arrested cells could also provide other survival signals through Erk-dependent transcription of survival proteins, such as Bcl-2, Bcl-xL, and Mcl-1 (6,29,45); however, Bcl-2 and Bcl-xL protein levels do not change upon G 1 /S arrest or detachment (data not shown).…”

Section: Discussionmentioning

confidence: 99%

G₁/S Cell Cycle Arrest Provides Anoikis Resistance through Erk-Mediated Bim Suppression

Collins

Reginato

Paulus

et al. 2005

Molecular and Cellular Biology

123

100

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Epidermal growth factor inhibition of c-Myc-mediated apoptosis through Akt and Erk involves Bcl-xL upregulation in mammary epithelial cells

Cited by 34 publications

References 44 publications

Galiximab Signals B-NHL Cells and Inhibits the Activities of NF-κB–Induced YY1- and Snail-Resistant Factors: Mechanism of Sensitization to Apoptosis by Chemoimmunotherapeutic Drugs

Galiximab Signals B-NHL Cells and Inhibits the Activities of NF-κB–Induced YY1- and Snail-Resistant Factors: Mechanism of Sensitization to Apoptosis by Chemoimmunotherapeutic Drugs

Agonists of an ecdysone-inducible mammalian expression system inhibit Fas Ligand- and TRAIL-induced apoptosis in the human colon carcinoma cell line RKO

G₁/S Cell Cycle Arrest Provides Anoikis Resistance through Erk-Mediated Bim Suppression

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Epidermal growth factor inhibition of c-Myc-mediated apoptosis through Akt and Erk involves Bcl-xL upregulation in mammary epithelial cells

Cited by 34 publications

References 44 publications

Galiximab Signals B-NHL Cells and Inhibits the Activities of NF-κB–Induced YY1- and Snail-Resistant Factors: Mechanism of Sensitization to Apoptosis by Chemoimmunotherapeutic Drugs

Galiximab Signals B-NHL Cells and Inhibits the Activities of NF-κB–Induced YY1- and Snail-Resistant Factors: Mechanism of Sensitization to Apoptosis by Chemoimmunotherapeutic Drugs

Agonists of an ecdysone-inducible mammalian expression system inhibit Fas Ligand- and TRAIL-induced apoptosis in the human colon carcinoma cell line RKO

G1/S Cell Cycle Arrest Provides Anoikis Resistance through Erk-Mediated Bim Suppression

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G₁/S Cell Cycle Arrest Provides Anoikis Resistance through Erk-Mediated Bim Suppression