It has become increasingly clear that deregulation of the NFκB signaling cascade is a common underlying feature of many human ailments including cancers. The past two decades of intensive research on NFκB has identified the basic mechanisms that govern the functioning of this pathway but uncovering the details of why this pathway works differently in different cellular contexts or how it interacts with other signaling pathways remains a challenge. A thorough understanding of these processes is needed to design better and more efficient therapeutic approaches to treat complex diseases like cancer. In this review, we summarize the literature documenting the involvement of NFκB in cancer, and then focus on the approaches that are being undertaken to develop NFκB inhibitors towards treatment of human cancers.

NFκB signaling in carcinogenesis and as a potential molecular target for cancer therapy

Identification of the active component and mechanisms of action of traditional medicines is highly desirable. We investigated whether zerumbone, a sesquiterpene from tropical ginger, can enhance the anticancer effects of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL). We found that zerumbone potentiated TRAIL-induced apoptosis in human HCT116 colon cancer cells and that this correlated with the up-regulation of TRAIL death receptor (DR) 4 and DR5. Induction of DRs occurred at the transcriptional level, and this induction was not cell-type specific, as its expression was also up-regulated in prostate, kidney, breast, and pancreatic cancer cell lines. Deletion of DR5 or DR4 by small interfering RNA significantly reduced the apoptosis induced by TRAIL and zerumbone. In addition to up-regulating DRs, zerumbone also significantly down-regulated the expression of cFLIP but not that of other antiapoptotic proteins. The induction of both DRs by zerumbone was abolished by glutathione and N-acetylcysteine (NAC), and this correlated with decreased TRAIL-induced apoptosis, suggesting a critical role of reactive oxygen species. Inhibition of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase but not of Jun NH2-terminal kinase abolished the effect of zerumbone on DRinduction. Zerumbone also induced the p53 tumor suppressor gene but was found to be optional for DRinduction or for enhancement of TR AIL-induced apoptosis. Both bax and p21, however, were required for zerumbone to stimulate TRAIL-induced apoptosis. Overall, our results show that zerumbone can potentiate TRAIL-induced apoptosis through the reactive oxygen species–mediated activation of extracellular signal-regulated kinase 1/2 and p38 mitogenactivated protein kinase leading to DR4 and DR5 induction and resulting in enhancement of the anticancer effects of TRAIL. [Cancer Res 2009;69(16):6581–9]

https://cancerres.aacrjournals.org/content/canres/69/16/6581.full.pdf

Zerumbone Enhances TRAIL-Induced Apoptosis through the Induction of Death Receptors in Human Colon Cancer Cells: Evidence for an Essential Role of Reactive Oxygen Species

Background 
PTEN-induced kinase 1 (PINK1) is linked to recessive Parkinsonism (EOPD). Pink1 deletion results in impaired dopamine (DA) release and decreased mitochondrial respiration in the striatum of mice. To reveal additional mechanisms of Pink1-related dopaminergic dysfunction, we studied Ca2+ vulnerability of purified brain mitochondria, DA levels and metabolism and whether signaling pathways implicated in Parkinson's disease (PD) display altered activity in the nigrostriatal system of Pink1−/− mice.


Methods and Findings 
Purified brain mitochondria of Pink1−/− mice showed impaired Ca2+ storage capacity, resulting in increased Ca2+ induced mitochondrial permeability transition (mPT) that was rescued by cyclosporine A. A subpopulation of neurons in the substantia nigra of Pink1−/− mice accumulated phospho-c-Jun, showing that Jun N-terminal kinase (JNK) activity is increased. Pink1−/− mice 6 months and older displayed reduced DA levels associated with increased DA turnover. Moreover, Pink1−/− mice had increased levels of IL-1β, IL-12 and IL-10 in the striatum after peripheral challenge with lipopolysaccharide (LPS), and Pink1−/− embryonic fibroblasts showed decreased basal and inflammatory cytokine-induced nuclear factor kappa-β (NF-κB) activity. Quantitative transcriptional profiling in the striatum revealed that Pink1−/− mice differentially express genes that (i) are upregulated in animals with experimentally induced dopaminergic lesions, (ii) regulate innate immune responses and/or apoptosis and (iii) promote axonal regeneration and sprouting.


Conclusions 
Increased mitochondrial Ca2+ sensitivity and JNK activity are early defects in Pink1−/− mice that precede reduced DA levels and abnormal DA homeostasis and may contribute to neuronal dysfunction in familial PD. Differential gene expression in the nigrostriatal system of Pink1−/− mice supports early dopaminergic dysfunction and shows that Pink1 deletion causes aberrant expression of genes that regulate innate immune responses. While some differentially expressed genes may mitigate neurodegeneration, increased LPS-induced brain cytokine expression and impaired cytokine-induced NF-κB activation may predispose neurons of Pink1−/− mice to inflammation and injury-induced cell death.

/pdf/increased-mitochondrial-calcium-sensitivity-and-abnormal-bmmwyh7cfp.pdf

Increased Mitochondrial Calcium Sensitivity and Abnormal Expression of Innate Immunity Genes Precede Dopaminergic Defects in Pink1-Deficient Mice

TRAILing death in cancer.

https://digitalcommons.unmc.edu/cgi/viewcontent.cgi?article=1021&context=com_bio_articles

Death Receptor 5 Signaling Promotes Hepatocyte Lipoapoptosis

Manipulation of TRAIL receptor 2 (DR5) pathway is a promising therapeutic strategy to overcome TRAIL-resistant lung cancer cells. Preclinical studies have shown that proteasome inhibitors enhance TRAIL-induced apoptosis in lung cancer cells, but the underlying mechanism has not been fully elucidated. In this study, we demonstrated the enhancement of TRAIL-mediated apoptosis in human alveolar epithelial cells by proteasome inhibitors that up-regulate DR5 expression. This effect was blocked by DR5-neutralizing Ab. Using reporter assay, we demonstrated that the p53 and NF-kappaB elements on the DR5 first intron region were involved in proteasome inhibitor-induced DR5 expression. Both p53 small interfering RNA and NF-kappaB inhibitor suppressed DR5 expression, strengthening the significance of p53 and NF-kappaB in DR5 transcription. The protein stability, Ser(392) phosphorylation and Lys(373)/Lys(382) acetylation of p53 were enhanced by MG132. In addition to p53, IkappaBalpha degradation and NF-kappaB translocation was also observed. Moreover, the binding of p53 and p65 to the first intron of DR5 was demonstrated by DNA affinity protein-binding and chromatin immunoprecipitation assays. Intracellular reactive oxygen species (ROS) generation after MG132 treatment contributed to p53, but not p65 nuclear translocation and DNA-binding activity. ROS scavenger dramatically inhibited the apoptosis induced by proteasome inhibitors plus TRAIL. The p53-null H1299 cells were resistant to proteasome inhibitor-induced DR5 up-regulation and enhancement of TRAIL-induced apoptosis. These findings reveal that proteasome inhibitor-mediated NF-kappaB and ROS-dependent p53 activation are contributed to intronic regulation of DR5 transcription, and resulted in the subsequent enhancement of TRAIL-induced apoptosis in human lung cancer cells.

Proteasome Inhibitors Enhance TRAIL-Induced Apoptosis through the Intronic Regulation of DR5: Involvement of NF-κB and Reactive Oxygen Species-Mediated p53 Activation

Proteasome Inhibitors Enhance TRAIL-Induced Apoptosis Through The Intronic Regulation Of DR5: Involvement Of NF-{kappa}B And Reactive Oxygen Species-Mediated p53 Activation

This information is current as Species-Mediated p53 Activation B and Reactive Oxygen κ NF-Regulation of DR5: Involvement of TRAIL-Induced Apoptosis through the Proteasome Inhibitors Enhance

Chia-Wei Chou

Papers

Proteasome Inhibitors Enhance TRAIL-Induced Apoptosis through the Intronic Regulation of DR5: Involvement of NF-κB and Reactive Oxygen Species-Mediated p53 Activation

Proteasome Inhibitors Enhance TRAIL-Induced Apoptosis Through The Intronic Regulation Of DR5: Involvement Of NF-{kappa}B And Reactive Oxygen Species-Mediated p53 Activation

This information is current as Species-Mediated p53 Activation B and Reactive Oxygen κ NF-Regulation of DR5: Involvement of TRAIL-Induced Apoptosis through the Proteasome Inhibitors Enhance