Therapeutic Modulation of Akt Activity and Antitumor Efficacy of Interleukin-12 Against Orthotopic Murine Neuroblastoma

Khan, Tahira; Hixon, Julie A.; Stauffer, Jimmy K.; Lincoln, Erin; Back, Timothy C.; Brenner, Jason; Lockett, Stephen; Nagashima, Kunio; Powell, Douglas; Wigginton, Jon M.

doi:10.1093/jnci/djj021

Cited by 13 publications

(13 citation statements)

References 73 publications

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“…We have shown previously that, although TBJ neuroblastoma cells express receptors for TNF-␣, they express no Fas and only negligible amounts of TRAIL-R2 (28). Treatment of TBJ cells with bortezomib (5 nM) for 24 h did not result in any changes in the cell surface expression of either Fas or TRAIL-R2, but did increase the expression of TNF-RI (control ϭ 11 Ϯ 5% vs bortezomib ϭ 44 Ϯ 20%) (Fig.…”

Section: Bortezomib Up-regulates Ifn-␥ and Tnf-␣ Receptor Expression mentioning

confidence: 68%

“…We have shown previously that TBJ and Neuro-2a murine neuroblastoma tumors are intrinsically resistant to receptor-mediated apoptosis (28). More specifically, these cells demonstrate limited expression of death receptors, including Fas and TRAIL-R2, and express high levels of phosphorylated Akt, a key anti-apoptotic factor (28).…”

Section: Bortezomib Inhibits Proliferation and Induces Apoptosis Of Mmentioning

confidence: 98%

“…More specifically, these cells demonstrate limited expression of death receptors, including Fas and TRAIL-R2, and express high levels of phosphorylated Akt, a key anti-apoptotic factor (28). In that proteasome inhibitors can both up-regulate the expression of proapoptotic genes (8,11,(17)(18)(19), and down-regulate the expression/activity of prosurvival factors, such as Akt in hematologic neoplasms (23,24), we hypothesized that bortezomib could mediate antitumor effects against neuroblastoma tumors as well.…”

Section: Bortezomib Inhibits Proliferation and Induces Apoptosis Of Mmentioning

confidence: 99%

“…Treatment with bortezomib induced apoptosis of murine neuroblastoma cells in conjunction with marked reductions in mitochondrial membrane potential. To directly investigate whether bortezomib also modulated the activation and subcellular translocation of Bid, TBJ cells were engineered to overexpress a commercially available fusion construct consisting of GFP fused to the C terminus of human Bid as described previously (TBJ-Bid-EGFP) (28). TBJ cells that overexpress unmodified GFP alone without Bid (TBJ-GFP) also were generated as an additional negative control cell.…”

Section: Bortezomib Inhibits Akt Phosphorylation and Induces Bid Tranmentioning

confidence: 99%

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Proteasome Inhibition to Maximize the Apoptotic Potential of Cytokine Therapy for Murine Neuroblastoma Tumors

Khan

Stauffer

Williams

et al. 2006

The Journal of Immunology

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Human neuroblastomas possess several mechanisms of self-defense that may confer an ability to resist apoptosis and contribute to the observed difficulty in treating these tumors in the clinical setting. These molecular alterations may include defects in proapoptotic genes as well as the overexpression of prosurvival factors, such as Akt among others. As a key regulator of the turnover of proteins that modulate the cell cycle and mechanisms of apoptosis, the proteasome could serve as an important target for the treatment of neuroblastoma. The present studies provide the first evidence that bortezomib, a newly approved inhibitor of proteasome function, inhibits phosphorylation of Akt, induces the translocation of proapoptotic Bid, and potently enhances the apoptosis of murine neuroblastoma tumor cells in vitro. Furthermore, in that inhibitors of the Akt pathway can sensitize otherwise resistant TBJ/Neuro-2a cells to apoptosis induced by IFN-γ plus TNF-α, we hypothesized that bortezomib also could sensitize these cells to IFN-γ plus TNF-α. We demonstrate for the first time that bortezomib not only up-regulates the expression of receptors for IFN-γ and TNF-α on both TBJ neuroblastoma and EOMA endothelial cell lines, but also markedly enhances the sensitivity of these cells to apoptosis induced by IFN-γ plus TNF-α in vitro. Furthermore, bortezomib enhances the in vivo antitumor efficacy of IFN-γ/TNF-α-inducing cytokines, including both IL-2 and IL-12 in mice bearing well-established primary and/or metastatic TBJ neuroblastoma tumors. Collectively, these studies suggest that bortezomib could be used therapeutically to enhance the proapoptotic and overall antitumor activity of systemic cytokine therapy in children with advanced neuroblastoma.

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Section: Bortezomib Up-regulates Ifn-␥ and Tnf-␣ Receptor Expression mentioning

confidence: 68%

Section: Bortezomib Inhibits Proliferation and Induces Apoptosis Of Mmentioning

confidence: 98%

Section: Bortezomib Inhibits Proliferation and Induces Apoptosis Of Mmentioning

confidence: 99%

Section: Bortezomib Inhibits Akt Phosphorylation and Induces Bid Tranmentioning

confidence: 99%

See 2 more Smart Citations

Proteasome Inhibition to Maximize the Apoptotic Potential of Cytokine Therapy for Murine Neuroblastoma Tumors

Khan

Stauffer

Williams

et al. 2006

The Journal of Immunology

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“…IL-12 is a proinflammatory cytokine secreted by dendritic cells that, among other functions, promotes cytotoxic T cell and NK cell activity (17). The anti-tumor effects of IL-12 have been studied previously by administering recombinant IL-12 into a mouse model of neuroblastoma (18), and others have explored ex vivo modification of cells with Ad-IL12 vectors to induce an anti-tumor immune response after infusion into animal models of neuroblastoma (19) and glioblastoma (20). Although clinical application of IL-12 therapy has thus far not demonstrated robust efficacy (21), achieving higher levels of IL-12 expression in ex vivo modified immune cells or within the tumor itself could potentially enhance tumor killing in vivo using this strategy.…”

Section: Adenoviral (Ad)mentioning

confidence: 99%

The Liberation of CD44 Intracellular Domain Modulates Adenoviral Vector Transgene Expression

Ildefonso

Bond

Altawashi

et al. 2012

Journal of Biological Chemistry

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Background: Hyaluronan-CD44 interaction enhances expression of adenoviral vector transgenes. Results: Inhibition of CD44 targeting proteases blocks enhancement of vector transgene expression and liberated intracellular domain enhances expression. Conclusion: CD44 proteolysis plays a role in the modulation of adenoviral vector transgene expression. Significance: Understanding the role of CD44 signaling in enhancement of transcription of adenoviral genes will be beneficial in viral gene transfer applications.

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Regulation of a truncated isoform of AMP-activated protein kinase α (AMPKα) in response to hypoxia in the muscle of Pacific oyster Crassostrea gigas

et al. 2013

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AMP-activated protein kinase α (AMPKα) is a key regulator of energy balance in many model species during hypoxia. In a marine bivalve, the Pacific oyster Crassostrea gigas, we analyzed the protein content of adductor muscle in response to hypoxia during 6 h. In both smooth and striated muscles, the amount of full-length AMP-activated protein kinase α (AMPKα) remained unchanged during hypoxia. However, hypoxia induced a rapid and muscle-specific response concerning truncated isoforms of AMPKα. In the smooth muscle, a truncated isoform of AMPKα was increased from 1 to 6 h of hypoxia, and was linked with accumulation of AKT kinase, a key enzyme of the insulin signaling pathway which controls intracellular glucose metabolism. In this muscle, aerobic metabolism was maintained over the 6 h of hypoxia, as mitochondrial citrate synthase activity remained constant. In contrast, in striated muscle, hypoxia did not induce any significant modification of neither truncated AMPKα nor AKT protein content, and citrate synthase activity was altered after 6 h of hypoxia. Together, our results demonstrate that hypoxia response is specific to muscle type in Pacific oyster, and that truncated AMPKα and AKT proteins might be involved in maintaining aerobic metabolism in smooth muscle. Such regulation might occur in vivo during tidal intervals that cause up to 6 h of hypoxia.

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Therapeutic Modulation of Akt Activity and Antitumor Efficacy of Interleukin-12 Against Orthotopic Murine Neuroblastoma

Abstract: Our results suggest that IL-12 overcomes a potentially critical mechanism of tumor self-defense in vivo by inhibiting Akt activity and imply that IL-12 may possess unique therapeutic activity against tumors that express high levels of activated Akt.

Cited by 13 publications

References 73 publications

Proteasome Inhibition to Maximize the Apoptotic Potential of Cytokine Therapy for Murine Neuroblastoma Tumors

Proteasome Inhibition to Maximize the Apoptotic Potential of Cytokine Therapy for Murine Neuroblastoma Tumors

The Liberation of CD44 Intracellular Domain Modulates Adenoviral Vector Transgene Expression

Regulation of a truncated isoform of AMP-activated protein kinase α (AMPKα) in response to hypoxia in the muscle of Pacific oyster Crassostrea gigas

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