Pharmacological inhibitors of NF-κB accelerate apoptosis in chronic lymphocytic leukaemia cells

Pickering, Becky M.; Mel, Sanjay de; Lee, M; Howell, Melanie; Habens, Fay; Dallman, Claire L.; Neville, Louise A.; Potter, K N; Mann, Jelena; Mann, Derek A.; Johnson, Peter; Stevenson, Freda K.; Packham, Graham

doi:10.1038/sj.onc.1209897

Cited by 72 publications

(57 citation statements)

References 58 publications

(81 reference statements)

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“…Indeed, p38, JNK and Akt converge to the LAIR-1-mediated inhibition of B-cell proliferation A Poggi et al activation of transcription factors, such as NF-kB, which may lead to cell survival and proliferation. 5,6,24,34,35 We have previously reported that LAIR-1 can inhibit proliferation of acute myeloid leukaemia blasts induced by growth factors, by preventing NF-kB nuclear translocation, and this effect is ITIMdependent. 17,18 Along this line, we observed that LAIR-1 engagement blocks both constitutive and sIgM-induced NF-kB activation in CLL.…”

Section: Discussionmentioning

confidence: 99%

Lack of the leukocyte-associated Ig-like receptor-1 expression in high-risk chronic lymphocytic leukaemia results in the absence of a negative signal regulating kinase activation and cell division

Poggi¹,

Catellani

Bruzzone

et al. 2008

Leukemia

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In this study, we analysed 30 patients with B-cell chronic lymphocytic leukaemia (CLL), compared with 10 healthy donors, for the expression and function of the leukocyteassociated Ig-like receptor-1 (LAIR-1). LAIR-1 is an inhibitory receptor containing a cytoplasmic tyrosine-based inhibitory motif (ITIM) that binds to the SH2 domain of phosphatases, leading to dephosphorylation of different kinases. Constitutive activation of c-Jun aminoterminal kinase (JNK), p38 mitogenactivated protein kinase and extracellular signal-regulated kinase, has been reported in CLL. We show that LAIR-1 is absent in high-risk (HR) CLL and differently expressed on intermediate-and low-risk CLL and the intensity of expression, which is always significantly lower than in healthy donors, correlates with disease stage and progression. Interestingly, both constitutive and sIgM-induced phosphorylation of p38 and JNK is inhibited by LAIR-1 through an ITIM-dependent signal, as demonstrated by the use of specific ITIM-binding peptides; importantly, this inhibitory signal is missing when LAIR-1 is not expressed as occurs in HR CLL. Moreover, engagement of LAIR-1 blocks constitutive and sIgM-induced Akt phosphorylation, besides nuclear factor j-B nuclear translocation, and prevents CLL division. These results suggest that CLL lacking LAIR-1 may miss one of the molecular mechanisms controlling B-cell activation and proliferation.

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Section: Discussionmentioning

confidence: 99%

Lack of the leukocyte-associated Ig-like receptor-1 expression in high-risk chronic lymphocytic leukaemia results in the absence of a negative signal regulating kinase activation and cell division

Poggi¹,

Catellani

Bruzzone

et al. 2008

Leukemia

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“…To further investigate the molecular events that determine the effect of dinaciclib on CLL cell survival, we measured the activation status of multiple pro-survival oncogenic signalling pathways that have been reported to be upregulated in B cell malignancies, such as STAT3, NF-κB, p38, PI3K/AKT and RAF/MEK/ERK (Cuní, et al 2004, Hazan-Halevy, et al 2010, Kawauchi, et al 2002, Ogasawara, et al 2003, Pickering, et al 2007, Ringshausen, et al 2002, Rozovski, et al 2014, Sainz-Perez, et al 2006. The phosphorylation level of STAT3 (Tyr705), IκBα (Ser32/36), p38 (Thr180/Tyr182), AKT (Ser473) and ERK (Thr202/Tyr204) were assessed as markers of activation of these pathways in MEC-1.…”

Section: Dinaciclib Inhibits Pro-survival Signals In Cll Cellsmentioning

confidence: 99%

“…Once engaged, it activates pro-survival signals such as the RAF/MEK/ERK, PI3K/AKT, p38, NF-κB and STAT3 pathways, which play a pathogenic role in CLL (Cuní, et al 2004, Hazan-Halevy, et al 2010, Kawauchi, et al 2002, Ogasawara, et al 2003, Pickering, et al 2007, Ringshausen, et al 2002, Rozovski, et al 2014, Sainz-Perez, et al 2006. Nearly half of CLL cases have high levels of constitutively phosphorylated ERK1/2 (Muzio, et al 2008) and in freshly isolated CLL cells, phosphorylated p38 is predominately activated (Sainz-Perez, et al 2006).…”

Section: Introductionmentioning

confidence: 99%

Pro‐survival signal inhibition by CDK inhibitor dinaciclib in Chronic Lymphocytic Leukaemia

et al. 2016

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Short title: Effects of Dinaciclib on pro-survival signals in CLL. 2 SUMMARYDinaciclib is a cyclin-dependent kinase inhibitor with clinical potential in different cancers, including Chronic Lymphocytic Leukemia (CLL). In order to better understand its cytotoxic action, we characterized its effects on signalling pathways important for the survival of CLL cells. We found that dinaciclib induced apoptosis through the activation of caspases 8 and 9, which was independent of the presence of cytokines to mimic the environment of proliferation centres or IGVH mutation status. Moreover, treatment with dinaciclib led to the inhibition of oncogenic pathways normally activated in stimulated CLL cells, such as STAT3, NF-κB and p38. Also, PI3K/AKT and RAF/MEK/ERK pathways showed a transient and early activation, followed by a later, permanent inhibition. Dinaciclib was also able to block the expression of anti-apoptotic proteins of the BCL-2 family such as MCL-1 and BCL-xL. Finally, we show that low concentrations of dinaciclib enhanced cell sensitivity to ibrutinib and BCL-2 inhibitor ABT-199, two drugs with known effects on CLL. Taken together, our data show that dinaciclib targets multiple pro-survival signalling pathways in CLL, which provides a mechanistic explanation for its potent induction of apoptosis. They also support a therapeutic application of CDK inhibitors in CLL in combination with other relevant targeted therapies.

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“…The proportion of cells in G1, S, or G2/ M phases of the cell cycle was calculated as a proportion of all cells in cycle, and the proportion of cells with <G1 content was calculated as a proportion of all cells. Apoptosis was analysed by annexin V/propidium iodide staining (Pickering et al 2007). …”

Section: Apoptosis and Cell Cyclementioning

confidence: 99%

Differential induction of apoptosis in human breast cancer cell lines by phenethyl isothiocyanate, a glutathione depleting agent

Alwi

Cavell

Donlevy

et al. 2012

Cell Stress and Chaperones

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Phenethyl isothiocyanate (PEITC) is a naturally occurring electrophile which depletes intracellular glutathione (GSH) levels and triggers accumulation of reactive oxygen species (ROS). PEITC is of considerable interest as a potential chemopreventive/chemotherapeutic agent, and in this work, we have investigated the effects of PEITC on human breast cancer cell lines. Whereas PEITC readily induced apoptosis in MDA-MB-231 cells (associated with rapid activation of caspases 9 and 3, and decreased expression of BAX), MCF7 cells were relatively resistant to the apoptosis promoting effects of PEITC. The relative resistance of MCF7 cells was associated with high basal expression of NRF2, a transcription factor that coordinates cellular protective responses to oxidants and electrophiles and raised intracellular levels of GSH. This raised basal expression of NRF2 appeared to be a response to on-going production of ROS, since treatment with the antioxidant and GSH precursor N-acetylcysteine (NAC) reduced NRF2 expression. Moreover, pre-treatment of MDA-MB-231 cells with NAC rendered these cells relatively resistant to PEITC-induced apoptosis. In summary, our data confirm that PEITC may be an effective chemopreventive/therapeutic agents for breast cancer. However, differences in the basal expression of NRF2 and resultant changes in GSH levels may be an important determinant of sensitivity to PEITC-induced apoptosis.

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Pharmacological inhibitors of NF-κB accelerate apoptosis in chronic lymphocytic leukaemia cells

Cited by 72 publications

References 58 publications

Lack of the leukocyte-associated Ig-like receptor-1 expression in high-risk chronic lymphocytic leukaemia results in the absence of a negative signal regulating kinase activation and cell division

Lack of the leukocyte-associated Ig-like receptor-1 expression in high-risk chronic lymphocytic leukaemia results in the absence of a negative signal regulating kinase activation and cell division

Pro‐survival signal inhibition by CDK inhibitor dinaciclib in Chronic Lymphocytic Leukaemia

Differential induction of apoptosis in human breast cancer cell lines by phenethyl isothiocyanate, a glutathione depleting agent

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