The regulation of the JNK cascade and programmed cell death by NF-κB: mechanisms and functions

The nuclear factor κB (NF-κB) family is an evolutionarily conserved family of transcription factors that play a central role in immune and inflammatory responses. They also play a pivotal role in cell survival, whereby activation of NF-κB antagonizes programmed cell death induced by tumor necrosis factor receptors and other cell death signals. The prosurvival function of NF-κB has been implicated in a wide range of biological processes, including the development and homeostasis of the immune system and liver. It has also been implicated in the pathogenesis of numerous diseases, including cancer, chronic inflammation, and certain hereditary disorders. The protective activity of NF-κB can also hamper tumor cell killing inflicted by radiation or chemotherapeutic drugs, thereby promoting resistance to cancer treatments. This prosurvival activity of NF-κB involves the suppression of sustained c-Jun N-terminal kinase (JNK) activation and of the accumulation of cytotoxic reactive oxygen species. NF-κB mediates this function by inducing the transcription of target genes, whose products inhibit the JNK signaling pathway and suppress accumulation of reactive oxygen species through their antioxidant functions. The development of specific inhibitors that target the critical downstream NF-κB-regulated genes that promote survival in cancer and other diseases potentially holds a key to developing specific and effective therapeutic strategies to combat these disorders

Rewired lipid metabolism as an actionable vulnerability of aggressive colorectal carcinoma

Cancer cells reprogram lipid metabolism to fuel cell division, adaptation to stress, and metastatic dissemination. NF-κB transcription factors control this mechanism in aggressive Consensus Molecular Subtype (CMS)4 of colorectal carcinoma (CRC) via triacylglycerol (TAG) lipase, carboxylesterase 1 (CES1), thereby linking obesity-associated inflammation with metabolic adaptation and cytoprotection from lipid-induced toxicity. Our findings identify a potential therapeutic route to treat patients with metastasis-prone CRC and provide an example for targeting core tumor subtype-based vulnerabilities in cancers beyond CR

NF-κB: blending metabolism, immunity, and inflammation

The procurement and management of nutrients and ability to fight infections are fundamental requirements for survival. These defense responses are bioenergetically costly, requiring the immune system to balance protection against pathogens with the need to maintain metabolic homeostasis. NF-κB transcription factors are central regulators of immunity and inflammation. Over the last two decades, these factors have emerged as a pivotal node coordinating the immune and metabolic systems in physiology and the etiopathogenesis of major threats to human health, including cancer, autoimmunity, chronic inflammation, and others. In this review, we discuss recent advances in understanding how NF-κB-dependent metabolic programs control inflammation, metabolism, and immunity and how improved knowledge of them may lead to better diagnostics and therapeutics for widespread human diseases

Unlocking the NF-κB Conundrum: Embracing Complexity to Achieve Specificity.

Transcription factors of the nuclear factor κB (NF-κB) family are central coordinating regulators of the host defence responses to stress, injury and infection. Aberrant NF-κB activation also contributes to the pathogenesis of some of the most common current threats to global human health, including chronic inflammatory diseases, autoimmune disorders, diabetes, vascular diseases and the majority of cancers. Accordingly, the NF-κB pathway is widely considered an attractive therapeutic target in a broad range of malignant and non-malignant diseases. Yet, despite the aggressive efforts by the pharmaceutical industry to develop a specific NF-κB inhibitor, none has been clinically approved, due to the dose-limiting toxicities associated with the global suppression of NF-κB. In this review, we summarise the main strategies historically adopted to therapeutically target the NF-κB pathway with an emphasis on oncology, and some of the emerging strategies and newer agents being developed to pharmacologically inhibit this pathway

Urban biowaste-derived sensitizing materials for caffeine photodegradation

[EN] Caffeine-photosensitized degradation has been studied in the presence of bio-based materials derived from urban biowaste after aerobic aging. A peculiar fraction (namely bio-based substances (BBSs)), soluble in all the pH range, has been used as photosensitizing agent. Several caffeine photodegradation tests have been performed, and positive results have been obtained in the presence of BBSs and H2O2, without and with additional Fe(II) (photo-Fenton-like process). Moreover, hybrid magnetite-BBS nanoparticles have been synthesized and characterized, in order to improve the sensitizer recovery and reuse after the caffeine degradation. In the presence of such nanoparticles and H2O2 and Fe(II), the complete caffeine degradation has been attained in very short time. Both homogeneous and heterogeneous processes were run at pH = 5, milder condition compared to the classic photo-Fenton process.This work was performed with the financial support for academic interchange by the Marie Sklodowska-Curie Research and Innovation Staff Exchange project funded by the European Commission H2020-MSCA-RISE-2014 within the framework of the research project MAT4TREAT (project number 645551). Compagnia di San Paolo and University of Torino are gratefully acknowledged for funding Project Torino_call2014_L2_126 through BBando per il finanziamento di progetti di ricerca di Ateneo – anno 2014 (Project acronym: Microbusters). Additionally, authors would like to acknowledge Dr. Flavio R. Sives (La Plata, Argentina) for magnetization measurements.Prevot, AB.; Baino, F.; Fabbri, D.; Franzoso, F.; Magnacca, G.; Nistico, R.; Arques Sanz, A. (2017). Urban biowaste-derived sensitizing materials for caffeine photodegradation. Environmental Science and Pollution Research. 24(14):12599-12607. https://doi.org/10.1007/s11356-016-7763S1259912607241

The immunodominant 90-kilodalton protein is localized on the terminal tip structure of Mycoplasma pneumoniae.

Immunoblot analysis of convalescent-phase sera of experimentally infected chimpanzees or monoclonal antibodies (MAbs) specific to the 90- and 40-kDa proteins of Mycophasma pneumoniae indicated that both proteins were present in cytadsorbing, pathogenic strains PI-1428, M129, and FH but absent in noncytadsorbing, nonpathogenic strain M129-B176. Adsorption of convalescent-phase chimpanzee sera with virulent strain PI-1428 removed reactivity, whereas adsorption with avirulent strain M129-B176 did not remove reactivity to these two proteins. By using proteolysis and specific MAbs, we demonstrated that the 90- and 40-kDa proteins were surface exposed. Immunoelectron microscopy employing specific MAbs showed that the 90-kDa protein is localized on the terminal tip attachment apparatus.Immunoblot analysis of convalescent-phase sera of experimentally infected chimpanzees or monoclonal antibodies (MAbs) specific to the 90- and 40-kDa proteins of Mycophasma pneumoniae indicated that both proteins were present in cytadsorbing, pathogenic strains PI-1428, M129, and FH but absent in noncytadsorbing, nonpathogenic strain M129-B176. Adsorption of convalescent-phase chimpanzee sera with virulent strain PI-1428 removed reactivity, whereas adsorption with avirulent strain M129-B176 did not remove reactivity to these two proteins. By using proteolysis and specific MAbs, we demonstrated that the 90- and 40-kDa proteins were surface exposed. Immunoelectron microscopy employing specific MAbs showed that the 90-kDa protein is localized on the terminal tip attachment apparatus

Probing the interaction interface of the GADD45β/MKK7 and MKK7/DTP3 complexes by chemical cross-linking mass spectrometry

GADD45β is selectively and constitutively expressed in Multiple Myeloma cells, and this expression correlates with an unfavourable clinical outcome. GADD45β physically interacts with the JNK kinase, MKK7, inhibiting its activity to enable the survival of cancer cells. DTP3 is a small peptide inhibitor of the GADD45β/MKK7 complex and is able to restore MKK7/JNK activation, thereby promoting selective cell death of GADD45β-overexpressing cancer cells. Enzymatic MS foot-printing and diazirine-based chemical cross-linking MS (CX-MS) strategies were applied to study the interactions between GADD45β and MKK7 kinase domain (MKK7_KD) and between DTP3 and MKK7_KD. Our data show that the binding between GADD45β and MKK7 largely occurs between GADD45β loop 2 (region 103–117) and the kinase enzymatic pocket. We also show that DTP3 interferes with this GADD45β/MKK7 interaction by contacting the MKK7 peptides, 113–136 and 259–274. Accordingly, an MKK7_KD Δ(101–136) variant lacking Trp135 did not produce a fluorescence quenching effect upon the binding of DTP3. The assessment of the interaction between GADD45β and MKK7 and the elucidation of the recognition surfaces between DTP3 and MKK7 significantly advance the understanding of the mechanism underlying the inhibition of the GADD45β/MKK7 interaction by DTP3 and pave the way to the design of small-molecule DTP3 analogues

The NF-κB pharmacopeia: novel strategies to subdue an intractable target

NF-κB transcription factors are major drivers of tumor initiation and progression. NF-κB signaling is constitutively activated by genetic alterations or environmental signals in many human cancers, where it contributes to almost all hallmarks of malignancy, including sustained proliferation, cell death resistance, tumor-promoting inflammation, metabolic reprogramming, tissue invasion, angiogenesis, and metastasis. As such, the NF-κB pathway is an attractive therapeutic target in a broad range of human cancers, as well as in numerous non-malignant diseases. Currently, however, there is no clinically useful NF-κB inhibitor to treat oncological patients, owing to the preclusive, on-target toxicities of systemic NF-κB blockade. In this review, we discuss the principal and most promising strategies being developed to circumvent the inherent limitations of conventional IκB kinase (IKK)/NF-κB-targeting drugs, focusing on new molecules that target upstream regulators or downstream effectors of oncogenic NF-κB signaling, as well as agents targeting individual NF-κB subunits

Co-activation of NF-κB and MYC renders cancer cells addicted to IL6 for survival and phenotypic stability

NF-κB and MYC are found co-deregulated in human B and plasma-cell cancers. In physiology, NF-κB is necessary for terminal B-to-plasma cell differentiation, whereas MYC repression is required. It is thus unclear if NF-κB/MYC co-deregulation is developmentally compatible in carcinogenesis and/or impacts cancer cell differentiation state, possibly uncovering unique sensitivities. Using a mouse system to trace cell lineage and oncogene activation we found that NF-κB/MYC co-deregulation originated cancers with a plasmablast-like phenotype, alike human plasmablastic-lymphoma and was linked to t(8;14)[MYC-IGH] multiple myeloma. Notably, in contrast to NF-κB or MYC activation alone, co-deregulation rendered cells addicted to IL6 for survival and phenotypic stability. We propose that conflicting oncogene-driven differentiation pressures can be accommodated at a cost in poorly-differentiated cancers. SIGNIFICANCE: Our studies improve the understanding of cancer pathogenesis by demonstrating that co-deregulation of NF-κB and MYC synergize in forming a cancer with a poorly-differentiated state. The cancers in the mouse system share features with human Plasmablastic lymphoma that has a dismal prognosis and no standard of care, and with t(8;14)[MYC-IGH] Multiple myeloma, which is in overall resistant to standard therapy. Notably, we found that NF-κB and MYC co-deregulation uniquely render cells sensitive to IL6 deprivation, providing a road-map for patient selection. Because of the similarity of the cancers arising in the compound mutant mouse model with that of human Plasmablastic lymphoma and t(8;14)[MYC-IGH] Multiple myeloma, this model could serve in preclinical testing to investigate novel therapies for these hard-to-treat diseases

Poly(ADP-ribose) polymerase family member 14 (PARP14) is a novel effector of the JNK2-dependent pro-survival signal in multiple myeloma

Copyright @ 2013 Macmillan Publishers Limited. This is the author's accepted manuscript. The final published article is available from the link below.Regulation of cell survival is a key part of the pathogenesis of multiple myeloma (MM). Jun N-terminal kinase (JNK) signaling has been implicated in MM pathogenesis, but its function is unclear. To elucidate the role of JNK in MM, we evaluated the specific functions of the two major JNK proteins, JNK1 and JNK2. We show here that JNK2 is constitutively activated in a panel of MM cell lines and primary tumors. Using loss-of-function studies, we demonstrate that JNK2 is required for the survival of myeloma cells and constitutively suppresses JNK1-mediated apoptosis by affecting expression of poly(ADP-ribose) polymerase (PARP)14, a key regulator of B-cell survival. Strikingly, we found that PARP14 is highly expressed in myeloma plasma cells and associated with disease progression and poor survival. Overexpression of PARP14 completely rescued myeloma cells from apoptosis induced by JNK2 knockdown, indicating that PARP14 is critically involved in JNK2-dependent survival. Mechanistically, PARP14 was found to promote the survival of myeloma cells by binding and inhibiting JNK1. Moreover, inhibition of PARP14 enhances the sensitization of MM cells to anti-myeloma agents. Our findings reveal a novel regulatory pathway in myeloma cells through which JNK2 signals cell survival via PARP14, and identify PARP14 as a potential therapeutic target in myeloma.Kay Kendall Leukemia Fund, NIH, Cancer Research UK, Italian Association for Cancer Research and the Foundation for Liver Research