Molecularly-Targeted Strategy and NF-^|^kappa;B in Lymphoid Malignancies

Horie, Ryouichi

doi:10.3960/jslrt.53.185

Cited by 11 publications

(11 citation statements)

References 105 publications

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“…Our results suggest that the RelA NF-kB transcription factor has an important role in OCCC development and progression. Constitutive activation of NF-kB has been observed in many types of cancers, especially hematological cancers (Horie, 2013). In these tumors, NF-kB is usually activated by mutations of genes that directly regulate NF-kB.…”

Section: Gain Of Rela Activation Drives Aberrant Cytokine Gene Inductmentioning

confidence: 99%

Loss of HDAC-Mediated Repression and Gain of NF-κB Activation Underlie Cytokine Induction in ARID1A- and PIK3CA-Mutation-Driven Ovarian Cancer

Kim

Zhang

2016

Cell Reports

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ARID1A is frequently mutated in ovarian clear cell carcinoma (OCCC) and often co-exists with activating mutations of PIK3CA. Although induction of pro-inflammatory cytokines has been observed in this cancer, the mechanism by which the two mutations synergistically activate cytokine genes remains elusive. Here, we established an in vitro model of OCCC by introducing ARID1A knockdown and mutant PIK3CA into a normal human ovarian epithelial cell line, resulting in cell transformation and cytokine gene induction. We demonstrate that loss of ARID1A impairs the recruitment of the Sin3A-HDAC complex, while the PIK3CA mutation releases RelA from IκB, leading to cytokine gene activation. We show that an NF-κB inhibitor partly attenuates the proliferation of OCCC and improves the efficacy of carboplatin both in cell culture and in a mouse model. Our study thus reveals the mechanistic link between ARID1A/PIK3CA mutations and cytokine gene induction in OCCC and suggests that NF-κB inhibition could be a potential therapeutic option.

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Section: Gain Of Rela Activation Drives Aberrant Cytokine Gene Inductmentioning

confidence: 99%

Loss of HDAC-Mediated Repression and Gain of NF-κB Activation Underlie Cytokine Induction in ARID1A- and PIK3CA-Mutation-Driven Ovarian Cancer

Kim

Zhang

2016

Cell Reports

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“…Currently, over 800 compounds have been proposed to modulate NF-κB signaling, directly or indirectly, in different biologic contexts (3, 23). In addition, NF-κB is just one of several promising pathways currently being explored for targeted therapies.…”

Section: Resultsmentioning

confidence: 99%

“…Similarly, overexpression of a dominant negative IκBα in syngeneic murine AML models driven by MLL-AF9, MOZ-TIF or BCR-ABL/NUP98-HOXA9 resulted in prolonged survival (2). A plethora of inhibitors of NF-κB signaling have been reported (3). These include compounds with broad biological activity such as anti-oxidants, anti-inflammatory agents or proteasome inhibitors, and specific inhibitors of IKK phosphorylation / degradation.…”

Section: Introductionmentioning

confidence: 99%

“…These include compounds with broad biological activity such as anti-oxidants, anti-inflammatory agents or proteasome inhibitors, and specific inhibitors of IKK phosphorylation / degradation. However, NF-κB is a broadly active pathway, and IKK inhibitors may have off target effects (3). Inhibition of NF-κB specifically in leukemia cells may therefore be desirable.…”

Section: Introductionmentioning

confidence: 99%

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Transient potential receptor melastatin-2 (Trpm2) does not influence murine MLL-AF9-driven AML leukemogenesis or in vitro response to chemotherapy

Haladyna

Pastuer

Riedel

et al. 2016

Experimental Hematology

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Transient potential receptor melastatin-2 (TRPM2) is a non-selective cationic, Ca2+ permeable transmembrane pore that is preferentially expressed in cells of the myeloid lineage, and modulates signaling pathways converging onto NF-kB. This is of potential interest for AML therapy, as NF-κB signaling is emerging as a key pathway mediating drug resistance and leukemia initiating cell survival in AML, and inhibition of NF-κB signaling has been shown to be synergistic with chemotherapy. TRPM2 is overexpressed in AML compared to normal bone marrow, with highest levels in the FAB M3-6 subtypes. To determine the effect of loss of Trpm2 in a defined genetic model, we established MLL-AF9 driven AML on a Trpm2−/− genetic background. Trpm2−/− MLL-AF9 leukemias displayed reduced NF-κB phosphorylation and nuclear translocation. In vivo primary and secondary recipients of Trpm2−/− MLL-AF9 leukemias showed increased latency compared to recipients of wild type leukemia cells. However, the difference in latency was small, and lost in tertiary transplants. The effect of loss of Trpm2 in a BCR-ABL/NUP98-HOXA9 fusion model was even smaller. Given reports that loss or inhibition of TRPM2 enhanced killing by DNA damaging agents in neuroblastoma, breast and prostate cancer cell lines, we exposed Trpm2−/− and Trpm2wt primary MLL-AF9 leukemias to doxorubicin, cytarabine and etoposide, but found no difference in IC50. The in vitro response to decitabine was also unaffected. In summary, TRPM2 does not seem to play a major role in myeloid leukemogenesis. In addition, loss of TRPM2 does not augment the cytotoxicity of standard AML chemotherapeutic agents.

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“…Although many NF-JB inhibitory drugs have been identified, none have been successfully translated into clinical medicine as specific NF-JB inhibitors. 17 During the past decade, many small-molecule inhibitors have been synthesized and evaluated for potential therapeutic activity and antineoplastic strategies. Some have shown promising antitumor activity in preclinical trials and are used clinically for cancer treatment.…”

mentioning

confidence: 99%

The Novel IκB Kinase β Inhibitor, IMD-0560, Has Potent Therapeutic Efficacy in Ovarian Cancer Xenograft Model Mice

Sawada

Hashimoto

Sawada³

et al. 2016

Int J Gynecol Cancer

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Molecularly-Targeted Strategy and NF-^|^kappa;B in Lymphoid Malignancies

Cited by 11 publications

References 105 publications

Loss of HDAC-Mediated Repression and Gain of NF-κB Activation Underlie Cytokine Induction in ARID1A- and PIK3CA-Mutation-Driven Ovarian Cancer

Loss of HDAC-Mediated Repression and Gain of NF-κB Activation Underlie Cytokine Induction in ARID1A- and PIK3CA-Mutation-Driven Ovarian Cancer

Transient potential receptor melastatin-2 (Trpm2) does not influence murine MLL-AF9-driven AML leukemogenesis or in vitro response to chemotherapy

The Novel IκB Kinase β Inhibitor, IMD-0560, Has Potent Therapeutic Efficacy in Ovarian Cancer Xenograft Model Mice

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