NF‐κB Inhibition Restores Sensitivity to Fas‐Mediated Apoptosis in Lymphoma Cell Lines

Meli, Maria; D’Alessandro, Natale; Tolomeo, Manlio; Rausa, L; Notarbartolo, Monica; Dusonchet, Luisa

doi:10.1196/annals.1299.041

Cited by 15 publications

(10 citation statements)

References 5 publications

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“…Our results demonstrate that lymphoma cell lines with NF-B-ca exhibited very limited induction of apoptosis through either the intrinsic or extrinsic pathways, in comparison to cells lacking NF-B activity. These results confirm and extend previous results (36)(37)(38)(39)(40). We also showed that the inhibition occurred early in the activation of both apoptotic cascades, because there was no apparent reduction in caspase 8 or 9 levels.…”

Section: Discussionsupporting

confidence: 93%

The role of NF-κB-1 and NF-κB-2-mediated resistance to apoptosis in lymphomas

Bernal‐Mizrachi

Lovly²,

Ratner

2006

Proc. Natl. Acad. Sci. U.S.A.

102

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The NF-B pathways have been implicated in tumorigenesis in several lymphoid malignancies, including non-Hodgkin's and Hodgkin's lymphomas. However, the antiapoptotic functions and the mechanism responsible for signaling through each NF-B pathway remain to be elucidated. In the current study, lymphoma cell lines with constitutively active NF-B were found to be resistant to inducers of the extrinsic and intrinsic apoptosis pathways. Resistance to cell death resulted from blocks early and late in the apoptosis cascade. Several NF-B target genes were overexpressed in these cell lines, including Bcl-xL, Fas-associated death domainlike IL-1␤-converting enzyme inhibitor protein, cellular inhibitor of apoptosis, and X inhibitor of apoptosis. Inhibition of the canonical or noncanonical NF-B pathways with small interfering RNAs or adenovirus expressing a stable form of inhibitor of NF-B (IB) enhanced sensitivity to apoptosis inducers and resulted in lower levels of Bcl-xL or Fas-associated death domain-like IL-1␤-converting enzyme inhibitor protein, cellular inhibitor of apoptosis, and X inhibitor of apoptosis. These findings demonstrate an important role of both NF-B pathways in mediating resistance to apoptosis and distinctive antiapoptotic downstream target gene profiles responsible for this effect.Epstein-Barr virus ͉ human T cell leukemia virus ͉ Tax

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Section: Discussionsupporting

confidence: 93%

The role of NF-κB-1 and NF-κB-2-mediated resistance to apoptosis in lymphomas

Bernal‐Mizrachi

Lovly²,

Ratner

2006

Proc. Natl. Acad. Sci. U.S.A.

102

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“…While we showed the NFκB activation, there was no change in apoptosis after inhibition of the NFκB pathway with SN50. Thus, inhibition of NFκB activation alone may not translate into an effective anti-apoptotic response in childhood ALL as it does in other malignancies [25][26][27].…”

Section: Discussionmentioning

confidence: 88%

Diverse pathways mediate chemotherapy-induced cell death in acute lymphoblastic leukemia cell lines

et al. 2006

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Cancer cell resistance to chemotherapy may be mediated by defects in apoptotic pathways. A prior study showed that in vivo apoptosis of Acute Lymphoblastic Leukemia (ALL) blasts in response to chemotherapy could occur through diverse pathways including both p53-dependent and -independent mechanisms. In this study we investigated the apoptotic response in more detail by using a panel of ALL cell lines that differed in respect to p53 status. Upon exposure to a uniform stimulus, expression of apoptotic proteins, including the effector caspase-3, varied among ALL cell lines partly depending on p53 transcriptional activity and caspase-8 activation. Although the expression and contribution to apoptosis differed among known members of the apoptotic pathway, apoptosis was universally mediated by mitochondrial depolarization. The NFkappaB pathway was activated in response to chemotherapy but NFkappaB inhibition appeared to not influence chemosensitivity. This study further documents the highly variable nature of cell death programs in ALL and provides the foundation for cell death pathway modulation to improve ALL cure rates without increasing chemotherapy-related toxicity.

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“…Recently, researchers have shown that inhibition of NF-nB activity restores sensitivity to Fas-mediated apoptosis (43,44). Treatment of breast cancer cells with Ad-MMP-9, radiation, or both induced caspase-dependent apoptosis, which is associated with the activation of several individual caspases.…”

Section: Discussionmentioning

confidence: 99%

Matrix metalloproteinase-9 Inhibition Down-Regulates Radiation-Induced Nuclear Factor-κB Activity Leading to Apoptosis in Breast Tumors

Kunigal¹,

Lakka²,

Joseph³

et al. 2008

Clinical Cancer Research

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Purpose: Novel strategies are needed to prevent the high mortality rates of several types of cancer.These high rates stem from tumor resistance to radiation therapy, which is thought to result from the induction of matrix metalloproteinases (MMP) and plasminogen activators. In the present study, we show that the modulation of MMP-9 expression, using adenoviral-mediated transfer of the antisense MMP-9 gene (MMP-9 adenoviral construct, Ad-MMP-9), affects breast cancer sensitivity to radiation. Experimental Design: In the present study, we used antisense Ad-MMP-9 to down-regulate the expression of MMP-9 in MDA MB 231 breast cancer cell lines in vitro before irradiation and subsequently incubated cells in hypoxic condition. In vivo studies were done with orthotopic breast tumors, and radiosensitivity was evaluated both in vitro and in vivo.Results: Ad-MMP-9 infection resulted in down-regulation of radiation-induced levels of hypoxiainducible factor 1a and MMP-9 under hypoxic conditions in MDA MB 231 breast cancer cells. In addition, Ad-MMP-9, in combination with radiation, decreased levels of the transcription factors nuclear factor-nB and activator protein 1, both of which contribute to the radioresistance of breast tumors. Finally, the triggering of the Fas^Fas ligand apoptotic cascade, which resulted in the cleavage of PARP-1 and caspase-10, caspase-3, and caspase-7, signifies the efficiency of combined treatment of Ad-MMP-9 and radiation. Treatment with Ad-MMP-9 plus radiation completely regressed tumor growth in orthotopic breast cancer model. Conclusions: In summary, integrating gene therapy (adenovirus-mediated inhibition of MMP-9) with radiotherapy could have a synergistic effect, thereby improving the survival of patients with breast cancer.

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NF‐κB Inhibition Restores Sensitivity to Fas‐Mediated Apoptosis in Lymphoma Cell Lines

Cited by 15 publications

References 5 publications

The role of NF-κB-1 and NF-κB-2-mediated resistance to apoptosis in lymphomas

The role of NF-κB-1 and NF-κB-2-mediated resistance to apoptosis in lymphomas

Diverse pathways mediate chemotherapy-induced cell death in acute lymphoblastic leukemia cell lines

Matrix metalloproteinase-9 Inhibition Down-Regulates Radiation-Induced Nuclear Factor-κB Activity Leading to Apoptosis in Breast Tumors

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