NF-κB/Rel-mediated regulation of apoptosis in hematologic malignancies and normal hematopoietic progenitors

Abstract

The activity of NF-jB/Rel transcription factors can downmodulate apoptosis in normal and neoplastic cells of the hematologic and other compartments, contributing in maintaining neoplastic clone survival and impairing response to therapy. Alterations in nfjb or ijB genes are documented in some hematologic neoplasias, while in others dysfunction in NF-jB/Rel-activating signaling pathways can be recognized. The prosurvival properties of NF-jB/Rel appear to rely on the induced expression of molecules (caspase inhibitors, Bcl2 protein family members, etc.), which interfere with the apoptosis pathway. Constitutive NF-jB/Rel activity in some hematologic malignancies could be advantageous for neoplastic clone expansion by counteracting stress stimuli (consumption of growth factors and metabolites) and immune system-triggered apoptosis; it is furthermore likely to play a central role in determining resistance to therapy. Based on this evidence, NFjB/Rel-blocking approaches have been introduced in antineoplastic strategies. The identification of NF-jB/Rel target genes relevant for survival in specific neoplasias is required in order to address tailored therapies and avoid possible detrimental effects due to widespread NF-jB/Rel inhibition. Moreover, comparative analyses of normal hematopoietic progenitors and neoplastic cell sensitivities to inhibitors of NF-jB/Rel and their target genes will allow to evaluate the impact of these tools on normal bone marrow. Regulation of apoptosis by NF-jB/Rel factors NF-kB/Rel transcription factors are dimers of proteins (p50/p105 or NF-kB1, p52/p100 or NF-kB2, p65 or RelA, c-Rel and RelB) containing an approximately 300 amino-acid REL homology domain (RHD), which mediates protein dimerization and binding to DNA. 1 The RHD is also involved in interacting with the ankyrin repeats of IkB, a family of proteins coevolved with NF-kB/Rel. 1,2 NF-kB/Rel dimers are retained in the cytoplasm of several cell types by inhibitors of the IkB family. Growth factors, cytokines, hormones or other agents can induce, through the IKK (IkB-kinase) cascade or other kinases, 1,2 the phosphorylation and ubiquitin-mediated degradation of the IkB proteins, allowing the NF-kB/Rel dimers to reach the nucleus. 3 NF-kB/Rel activation is also induced by stress stimuli that provoke increases in the intracellular concentration of reactive oxygen species (ROS), imbalance in calcium ions fluxes and/or accumulation of unfolded proteins in the endoplasmic reticulum (RE). Such events trigger the activation of stress kinases and other modulators, which ultimately lead to IkB degradation. [1][2][3]

Retinoid-induced activation of NF-κB in APL cells is not essential for granulocytic differentiation, but prolongs the life span of mature cells

“…However, since an extensive regulation of protein expression occurs at the translation level during granulocytic differentiation (Grolleau et al, 1999;Gebauer and Hentze, 2004), this study will require specific proteomic analysis. Aberrant NF-kB activity contributes to neoplastic clone survival and lower sensitivity to apoptosis in several hematologic malignancies (Turco et al, 2004). The fact that we could obtain viable NB4 cells expressing a super repressor of NF-kB activation suggests that a constitutive NF-kB activity is not the essential cause of leukemic cell survival in APL.…”

NF‐κB as a potential molecular target for cancer therapy

“…Moreover, the proteasome inhibitor PS-341 enhanced the chemosensitivity to CPT-11 [27], and curcumin enhanced the radiation-induced apoptosis in PC-3, a prostate cancer cell line [23]. However, because NF-κB inhibitors also enhance the chemotherapy-induced apoptosis of normal hematopoietic progenitors, the use of NF-κB inhibitors as adjuvants in chemotherapy could delay bone marrow recovery [148]. It should be considered that because NF-κB has a critical role in the activation of innate and adaptive immune responses, long-term use of NF-κB inhibitors is likely to be associated with a risk of immunodeficiency.…”

Targeting NF-κB in hematologic malignancies

“…58 Tax expression can promote phosphorylation and activation of IKKa and IKKb by the kinase NF-kB-inducing kinase (NIK), and/or can directly bind to IKKg. 59,60 Constitutive NF-kB has also been detected in HTLV-1-negative ATL, indicating the existence of Taxindependent mechanisms of NF-kB activation. 61 The expression of the NF-kB target genes XIAP, survivin, Bcl-2, and Bcl-X L has been measured in primary ATL cells.…”

“…Moreover, cell-permeable peptides preventing the oligomerization and auto-activation of two subdomains of IKK-g (NEMO) abrogate NF-kB activation and induce apoptosis in retinoblastoma cell lines. 60,85,86,87 It remains to be seen whether these technologies will open new perspectives for the treatment of hematologic malignancies.…”

“…Such NF-kB-targeted decoy phosphorothioate oligonucleotides did not significantly affect cell survival in B-CLL and AML, yet enhanced the apoptotic response to classical cytotoxic compounds. 60,85,86,97 However, NF-kB decoy oligonucleotides are relatively large and polar compounds, a fact that negatively affects their cellular uptake and bioavailability. 6 Thus, further drug design will be required to improve their clinical applicability.…”