scholarly journals Fangchinoline, a Bisbenzylisoquinoline Alkaloid can Modulate Cytokine-Impelled Apoptosis via the Dual Regulation of NF-κB and AP-1 Pathways

Molecules ◽  
2019 ◽  
Vol 24 (17) ◽  
pp. 3127 ◽  
Author(s):  
Young Yun Jung ◽  
Muthu K. Shanmugam ◽  
Arunachalam Chinnathambi ◽  
Sulaiman Ali Alharbi ◽  
Omar H.M. Shair ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Myeloid Leukemia ◽  
Nuclear Factor Κb ◽  
Molecular Techniques ◽  
Signaling Cascades ◽  
Activator Protein 1 ◽  
Iκb Kinase ◽  
Oncogenic Pathways ◽  
Bisbenzylisoquinoline Alkaloid ◽  
Athlete’S Foot

Fangchinoline (FCN) derived from Stephaniae tetrandrine S. Moore can be employed to treat fever, inflammation, rheumatism arthralgia, edema, dysuria, athlete’s foot, and swollen wet sores. FCN can exhibit a plethora of anti-neoplastic effects although its precise mode of action still remains to be deciphered. Nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) can closely regulate carcinogenesis and thus we analyzed the possible action of FCN may have on these two signaling cascades in tumor cells. The effect of FCN on NF-κB and AP-1 signaling cascades and its downstream functions was deciphered using diverse assays in both human chronic myeloid leukemia (KBM5) and multiple myeloma (U266). FCN attenuated growth of both leukemic and multiple myeloma cells and repressed NF-κB, and AP-1 activation through diverse mechanisms, including attenuation of phosphorylation of IκB kinase (IKK) and p65. Furthermore, FCN could also cause significant enhancement in TNFα-driven apoptosis as studied by various molecular techniques. Thus, FCN may exhibit potent anti-neoplastic effects by affecting diverse oncogenic pathways and may be employed as pro-apoptotic agent against various malignancies.

scholarly journals Formononetin Regulates Multiple Oncogenic Signaling Cascades and Enhances Sensitivity to Bortezomib in a Multiple Myeloma Mouse Model

Biomolecules ◽  
2019 ◽  
Vol 9 (7) ◽  
pp. 262 ◽  
Author(s):  
Chulwon Kim ◽  
Jong Hyun Lee ◽  
Jeong-Hyeon Ko ◽  
Arunachalam Chinnathambi ◽  
Sulaiman Ali Alharbi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Mouse Model ◽  
Nuclear Factor Κb ◽  
Signaling Cascades ◽  
Activator Protein 1 ◽  
Phosphatidylinositol 3 Kinase ◽  
Cellular Regulation ◽  
Oncogenic Signaling ◽  
Growth Inhibitory ◽  
Inhibitory Potential

Here, we determined the anti-neoplastic actions of formononetin (FT) against multiple myeloma (MM) and elucidated its possible mode of action. It was observed that FT enhanced the apoptosis caused by bortezomib (Bor) and mitigated proliferation in MM cells, and these events are regulated by nuclear factor-κB (NF-κB), phosphatidylinositol 3-kinase (PI3K)/AKT, and activator protein-1 (AP-1) activation. We further noted that FT treatment reduced the levels of diverse tumorigenic proteins involved in myeloma progression and survival. Interestingly, we observed that FT also blocked persistent NF-κB, PI3K/AKT, and AP-1 activation in myeloma cells. FT suppressed the activation of these oncogenic cascades by affecting a number of signaling molecules involved in their cellular regulation. In addition, FT augmented tumor growth-inhibitory potential of Bor in MM preclinical mouse model. Thus, FT can be employed with proteasomal inhibitors for myeloma therapy by regulating the activation of diverse oncogenic transcription factors involved in myeloma growth.

scholarly journals Biologic sequelae of IκB kinase (IKK) inhibition in multiple myeloma: therapeutic implications

Blood ◽  
2009 ◽  
Vol 113 (21) ◽  
pp. 5228-5236 ◽  
Author(s):  
Teru Hideshima ◽  
Dharminder Chauhan ◽  
Tanyel Kiziltepe ◽  
Hiroshi Ikeda ◽  
Yutaka Okawa ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Growth Inhibition ◽  
Cell Lines ◽  
Nuclear Factor Κb ◽  
Down Regulation ◽  
Growth And Survival ◽  
Therapeutic Implications ◽  
Iκb Kinase ◽  
Canonical Pathways ◽  
Promising Treatment

Abstract Nuclear factor-κB (NF-κB) has an important role in multiple myeloma (MM) cell pathogenesis in the context of the bone marrow (BM) microenvironment. In NF-κB signaling cascades, IκB kinase α (IKKα) and IKKβ are key molecules that predominantly mediate noncanonical and canonical pathways, respectively. In this study, we examined the biologic sequelae of the inhibition of IKKα versus IKKβ in MM cell lines. All MM cell lines have constitutive canonical NF-κB activity, and a subset of MM cell lines shows noncanonical NF-κB activity. Adhesion to BM stromal cells further activates both canonical and noncanonical NF-κB activity. IKKβ inhibitor MLN120B blocks canonical pathway and growth of MM cell lines but does not inhibit the noncanonical NF-κB pathway. Although IKKα knockdown induces significant growth inhibition in the cell lines with both canonical and noncanonical pathways, it does not inhibit NF-κB activation. Importantly, IKKα down-regulation decreases expression of β-catenin and aurora-A, which are known to mediate MM cell growth and survival. Finally, IKKβ inhibitor enhances the growth inhibition triggered by IKKα down-regulation in MM cells with both canonical and noncanonical NF-κB activity. Combination therapy targeting these kinases therefore represents a promising treatment strategy in MM.

scholarly journals NF-κB and AP-1 Connection: Mechanism of NF-κB-Dependent Regulation of AP-1 Activity

2004 ◽  
Vol 24 (17) ◽  
pp. 7806-7819 ◽  
Author(s):  
Shuichi Fujioka ◽  
Jiangong Niu ◽  
Christian Schmidt ◽  
Guido M. Sclabas ◽  
Bailu Peng ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Target Genes ◽  
Nuclear Factor Κb ◽  
Activator Protein 1 ◽  
Murine Embryonic Fibroblast ◽  
Downstream Target ◽  
Iκb Kinase ◽  
Extracellular Signal ◽  
Downstream Target Gene

ABSTRACT Nuclear factor κB (NF-κB) and activator protein 1 (AP-1) transcription factors regulate many important biological and pathological processes. Activation of NF-κB is regulated by the inducible phosphorylation of NF-κB inhibitor IκB by IκB kinase. In contrast, Fos, a key component of AP-1, is primarily transcriptionally regulated by serum responsive factors (SRFs) and ternary complex factors (TCFs). Despite these different regulatory mechanisms, there is an intriguing possibility that NF-κB and AP-1 may modulate each other, thus expanding the scope of these two rapidly inducible transcription factors. To determine whether NF-κB activity is involved in the regulation of fos expression in response to various stimuli, we analyzed activity of AP-1 and expression of fos, fosB, fra-1, fra-2, jun, junB, and junD, as well as AP-1 downstream target gene VEGF, using MDAPanc-28 and MDAPanc-28/IκBαM pancreatic tumor cells and wild-type, IKK1−/−, and IKK2−/− murine embryonic fibroblast cells. Our results show that elk-1, a member of TCFs, is one of the NF-κB downstream target genes. Inhibition of NF-κB activity greatly decreased expression of elk-1. Consequently, the reduced level of activated Elk-1 protein by extracellular signal-regulated kinase impeded constitutive, serum-, and superoxide-inducible c-fos expression. Thus, our study revealed a distinct and essential role of NF-κB in participating in the regulation of elk-1, c-fos, and VEGF expression.

scholarly journals Bortezomib induces canonical nuclear factor-κB activation in multiple myeloma cells

Blood ◽  
2009 ◽  
Vol 114 (5) ◽  
pp. 1046-1052 ◽  
Author(s):  
Teru Hideshima ◽  
Hiroshi Ikeda ◽  
Dharminder Chauhan ◽  
Yutaka Okawa ◽  
Noopur Raje ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Proteasome Inhibitors ◽  
Xenograft Model ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Down Regulation ◽  
Interacting Protein ◽  
Iκb Kinase

Bortezomib is a proteasome inhibitor with remarkable preclinical and clinical antitumor activity in multiple myeloma (MM) patients. The initial rationale for its use in MM was inhibition of nuclear factor (NF)-κB activity by blocking proteasomal degradation of inhibitor of κBα (IκBα). Bortezomib inhibits inducible NF-κB activity; however, its impact on constitutive NF-κB activity in MM cells has not yet been defined. In this study, we demonstrate that bortezomib significantly down-regulated IκBα expression and triggered NF-κB activation in MM cell lines and primary tumor cells from MM patients. Importantly, no inhibition of p65 (RelA) nuclear translocation was recognized after bortezomib treatment in a murine xenograft model bearing human MM cells. Bortezomib-induced NF-κB activation was mediated via the canonical pathway. Moreover, other classes of proteasome inhibitors also induced IκBα down-regulation associated with NF-κB activation. Molecular mechanisms whereby bortezomib induced IκBα down-regulation were further examined. Bortezomib triggered phosphorylation of IκB kinase (IKKβ) and its upstream receptor-interacting protein 2, whereas IKKβ inhibitor MLN120B blocked bortezomib-induced IκBα down-regulation and NF-κB activation, indicating receptor-interacting protein 2/IKKβ signaling plays crucial role in bortezomib-induced NF-κB activation. Moreover, IKKβ inhibitors enhanced bortezomib-induced cytotoxicity. Our studies therefore suggest that bortezomib-induced cytotoxicity cannot be fully attributed to inhibition of canonical NF-κB activity in MM cells.

Curcumin (diferuloylmethane) down-regulates the constitutive activation of nuclear factor–κB and IκBα kinase in human multiple myeloma cells, leading to suppression of proliferation and induction of apoptosis

Blood ◽  
2003 ◽  
Vol 101 (3) ◽  
pp. 1053-1062 ◽  
Author(s):  
Alok C. Bharti ◽  
Nicholas Donato ◽  
Sujay Singh ◽  
Bharat B. Aggarwal
Keyword(s):  
Multiple Myeloma ◽  
Cell Lines ◽  
Nuclear Factor Κb ◽  
Parp Cleavage ◽  
Nuclear Factor ◽  
Nuclear Retention ◽  
Iκb Kinase ◽  
Human Multiple Myeloma ◽  
Induction Of Apoptosis ◽  
Iκbα Phosphorylation

Abstract Because of the central role of the transcription factor nuclear factor–κB (NF-κB) in cell survival and proliferation in human multiple myeloma (MM), we explored the possibility of using it as a target for MM treatment by using curcumin (diferuloylmethane), an agent known to have very little or no toxicity in humans. We found that NF-κB was constitutively active in all human MM cell lines examined and that curcumin, a chemopreventive agent, down-regulated NF-κB in all cell lines as indicated by electrophoretic mobility gel shift assay and prevented the nuclear retention of p65 as shown by immunocytochemistry. All MM cell lines showed consitutively active IκB kinase (IKK) and IκBα phosphorylation. Curcumin suppressed the constitutive IκBα phosphorylation through the inhibition of IKK activity. Curcumin also down-regulated the expression of NF-κB–regulated gene products, including IκBα, Bcl-2, Bcl-xL, cyclin D1, and interleukin-6. This led to the suppression of proliferation and arrest of cells at the G1/S phase of the cell cycle. Suppression of NF-κB complex by IKKγ/NF-κB essential modulator-binding domain peptide also suppressed the proliferation of MM cells. Curcumin also activated caspase-7 and caspase-9 and induced polyadenosine-5′-diphosphate-ribose polymerase (PARP) cleavage. Curcumin-induced down-regulation of NF-κB, a factor that has been implicated in chemoresistance, also induced chemosensitivity to vincristine and melphalan. Overall, our results indicate that curcumin down-regulates NF-κB in human MM cells, leading to the suppression of proliferation and induction of apoptosis, thus providing the molecular basis for the treatment of MM patients with this pharmacologically safe agent.

scholarly journals Annexin-A1 SUMOylation regulates microglial polarization after cerebral ischemia by modulating IKKα stability via selective autophagy

2021 ◽  
Vol 7 (4) ◽  
pp. eabc5539
Author(s):  
Xing Li ◽  
Qian Xia ◽  
Meng Mao ◽  
Huijuan Zhou ◽  
Lu Zheng ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Underlying Mechanism ◽  
Nuclear Factor Κb ◽  
Annexin A1 ◽  
Selective Autophagy ◽  
Microglial Polarization ◽  
Proinflammatory Mediators ◽  
Therapeutic Benefits ◽  
Iκb Kinase ◽  
Ikk Complex

Annexin-A1 (ANXA1) has recently been proposed to play a role in microglial activation after brain ischemia, but the underlying mechanism remains poorly understood. Here, we demonstrated that ANXA1 is modified by SUMOylation, and SUMOylated ANXA1 could promote the beneficial phenotype polarization of microglia. Mechanistically, SUMOylated ANXA1 suppressed nuclear factor κB activation and the production of proinflammatory mediators. Further study revealed that SUMOylated ANXA1 targeted the IκB kinase (IKK) complex and selectively enhanced IKKα degradation. Simultaneously, we detected that SUMOylated ANXA1 facilitated the interaction between IKKα and NBR1 to promote IKKα degradation through selective autophagy. Further work revealed that the overexpression of SUMOylated ANXA1 in microglia/macrophages resulted in marked improvement in neurological function in a mouse model of cerebral ischemia. Collectively, our study demonstrates a previously unidentified mechanism whereby SUMOylated ANXA1 regulates microglial polarization and strongly indicates that up-regulation of ANXA1 SUMOylation in microglia may provide therapeutic benefits for cerebral ischemia.

scholarly journals Periprosthetic Osteolysis: Mechanisms, Prevention and Treatment

2019 ◽  
Vol 8 (12) ◽  
pp. 2091 ◽  
Author(s):  
Stuart B. Goodman ◽  
Jiri Gallo
Keyword(s):  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Activator Protein 1 ◽  
Periprosthetic Osteolysis ◽  
Bone Implant ◽  
Joint Replacements ◽  
In Vivo Experiments ◽  
Mechanical Factors

Clinical studies, as well as in vitro and in vivo experiments have demonstrated that byproducts from joint replacements induce an inflammatory reaction that can result in periprosthetic osteolysis (PPOL) and aseptic loosening (AL). Particle-stimulated macrophages and other cells release cytokines, chemokines, and other pro-inflammatory substances that perpetuate chronic inflammation, induce osteoclastic bone resorption and suppress bone formation. Differentiation, maturation, activation, and survival of osteoclasts at the bone–implant interface are under the control of the receptor activator of nuclear factor kappa-Β ligand (RANKL)-dependent pathways, and the transcription factors like nuclear factor κB (NF-κB) and activator protein-1 (AP-1). Mechanical factors such as prosthetic micromotion and oscillations in fluid pressures also contribute to PPOL. The treatment for progressive PPOL is only surgical. In order to mitigate ongoing loss of host bone, a number of non-operative approaches have been proposed. However, except for the use of bisphosphonates in selected cases, none are evidence based. To date, the most successful and effective approach to preventing PPOL is usage of wear-resistant bearing couples in combination with advanced implant designs, reducing the load of metallic and polymer particles. These innovations have significantly decreased the revision rate due to AL and PPOL in the last decade.

Localized pancreatic NF-κB activation and inflammatory response in taurocholate-induced pancreatitis

2001 ◽  
Vol 280 (6) ◽  
pp. G1197-G1208 ◽  
Author(s):  
Eva Vaquero ◽  
Ilya Gukovsky ◽  
Vjekoslav Zaninovic ◽  
Anna S. Gukovskaya ◽  
Stephen J. Pandol
Keyword(s):  
Transcription Factor ◽  
Inflammatory Response ◽  
Pancreatic Head ◽  
Pancreatic Injury ◽  
Nuclear Factor Κb ◽  
Saline Infusion ◽  
Activator Protein 1 ◽  
Local Inflammatory Response ◽  
Monocyte Chemoattractant Protein 1 ◽  
Factor Α

Transcription factor nuclear factor-κB (NF-κB) is activated in cerulein pancreatitis and mediates cytokine expression. The role of transcription factor activation in other models of pancreatitis has not been established. Here we report upregulation of NF-κB and inflammatory molecules, and their correlation with local pancreatic injury, in a model of severe pancreatitis. Rats received intraductal infusion of taurocholate or saline, and the pancreatic head and tail were analyzed separately. NF-κB and activator protein-1 (AP-1) activation were assessed by gel shift assay, and mRNA expression of interleukin-6, tumor necrosis factor-α, KC, monocyte chemoattractant protein-1, and inducible nitric oxide synthase was assessed by semiquantitative RT-PCR. Morphological damage and trypsin activation were much greater in the pancreatic head than tail, in parallel with a stronger activation of NF-κB and cytokine mRNA. Saline infusion mildly affected these parameters. AP-1 was strongly activated in both pancreatic segments after either taurocholate or saline infusion. NF-κB inhibition with N-acetylcysteine ameliorated the local inflammatory response. Correlation between localized NF-κB activation, cytokine upregulation, and tissue damage suggests a key role for NF-κB in the development of the inflammatory response of acute pancreatitis.

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