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

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

Mechanisms of liver disease: cross-talk between the NF-kappa B and JNK pathways

The liver plays a central role in the transformation anddegradation of endogenous and exogenous chemicals,and in the removal of unwanted cells such as damaged,genetically mutated and virus-infected cells. Because ofthis function, the liver is susceptible to toxicity causedby the products generated during these natural occur-rences. Hepatocyte death is the major feature of liverinjury. In response to liver injury, specific intracellularprocesses are initiated to maintain liver integrity. Inflam-matory cytokines including tumor necrosis factor (TNF)aand interleukin-6 (IL-6) are key mediators of these pro-cesses and activate different cellular response such asproliferation, survival and death. TNFainduces specificsignaling pathways in hepatocytes that lead to activationof either pro-survival mediators or effectors of cell death.Whereas activation of transcription factor NF-kBpro-motes survival, c-Jun N-terminal kinases (JNKs) andcaspases are strategic effectors of cell death in theTNFa-mediated signaling pathway. This review summa-rizes recent advances in the mechanisms of TNFa-induced hepatotoxicity and suggests that NF-kB plays aprotective role against JNK-induced hepatocyte death.Identification of the mechanisms regulating interplaybetween the NF-kB and JNK pathways is required in thesearch for novel targets for the treatment of liver disease,including hepatitis and hepatocellular carcinoma

The NF-kB-mediated control of ROS and JNK signaling

NF-kB/Rel transcription factors are best known for their roles in innate and adaptive immunity and inflammation. They also play a central role in promoting cell survival. This latter activity of NF-kB antagonizes programmed cell death (PCD) induced by the proinflammatory cytokine tumor necrosis factor (TNF)a and plays an important role in immunity, lymphopoiesis, osteogenesis, tumorigenesis and radioand chemo-resistance in cancer. With regard to TNFa, the NF-kB-mediated inhibition of PCD seems to involve an attenuation of the c-Jun-N-terminal kinase (JNK) cascade mediated through the induction of select downstream targets such as the caspase inhibitor XIAP, the zinc-finger protein A20, and the inhibitor of the MKK7/JNKK2 kinase, Gadd45ß/Myd118. Notably, NF- kB also blunts accumulation of reactive oxygen species (ROS), which themselves are pivotal elements for induction of PCD by TNFa, and this suppression of ROS formation mediates an additional protective activity recently ascribed to NF-kB. The antioxidant activity of NF-kB has been shown to depend upon upregulation of both Ferritin heavy chain (FHC) – a component of Ferritin, the primary iron-storage protein complex found in cells – and of the mitochondrial enzyme Mn++ superoxide dismutase (Mn-SOD). Indeed, the inductions of Mn-SOD and FHC represent another important means through which NF-kB controls proapoptotic JNK signaling triggered by TNFa. These findings might enable the development of new, more targeted approaches to treatment of diseases sustained by a deregulated activity of NF-kB, including some cancers and chronic inflammatory conditions