Critical role of NF-κB in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, and in spite of intense efforts there are limited therapeutic options for patients with PDAC. PDACs harbor a high frequency of Kras mutations and other driver mutations that lead to altered signaling pathways and contribute to therapeutic resistance. Importantly, constitutive activation of nuclear factor κB (NF-κB) is frequently observed in PDAC. An increasing body of evidence suggests that both classical and non-classical NF-κB pathways play a crucial role in PDAC development and progression. In this review, we update the most recent advances regarding different aspects of NF-κB involvement in PDAC development and progression, emphasizing its potential as a therapeutic target and the need to discover pathway-specific cytosolic NF-κB regulators which could be used to design novel therapeutic strategies for PDAC.     

Targeting NF-κB in mouse models of lung adenocarcinoma

Xue et al. demonstrate response and increased survival but development of acquired resistance to proteasome and inhibitor-κB kinase inhibitors targeting NF-κB activation in adenocarcinomas of Kras-activated, p53-deficient mice.     

IKK-dependent, NF-κB-independent control of autophagic gene expression

The induction of mammalian autophagy, a cellular catabolic bulk-degradation process conserved from humans to yeast, was recently shown to require IκB kinase (IKK), the upstream regulator of the nuclear factor (NF)-κB pathway. Interestingly, it was shown that this response did not involve NF-κB. Thus, the mechanism by which IKK promotes stimulus-induced autophagy is largely unknown. Here, we investigate the role of IKK/NF-κB in response to nutrient deprivation, the well-understood autophagy-inducing stimulus. IKK and both the classic and non-canonical pathways of NF-κB are robustly induced in response to cellular starvation. Notably, cells lacking either catalytic subunit of IKK (IKK-α or IKK-β) fail to induce autophagy in response to cellular starvation. Importantly, we show that IKK activity but not NF-κB controls basal expression of the proautophagic gene LC3. We further demonstrate that starvation induces the expression of LC3 and two other essential autophagic genes ATG5 and Beclin-1 in an IKK-dependent manner. These results indicate that the IKK complex is a central mediator of starvation-induced autophagy in mammalian cells, and suggest that this requirement occurs at least in part through the regulation of autophagic gene expression. Interestingly, NF-κB subunits are dispensable for both basal and starvation-induced expression of proautophagic genes. However, starvation-induced activation of NF-κB is not inconsequential, as increases in expression of antiapoptotic NF-κB target genes such as Birc3 are observed in response to cellular starvation. Thus, IKK likely has multiple roles in response to starvation by regulating NF-κB-dependent antiapoptotic gene expression as well as controlling expression of autophagic genes through a yet undetermined mechanism.     

A small molecule inhibitor of NF-κB,dehydroxymethylepoxyquinomicin (DHMEQ), suppresses growth and invasion of nasopharyngeal carcinoma (NPC) cells

Despite the demonstrated constitutive activation of NF-κB in nasopharyngeal carcinoma (NPC), the therapeutic potential of targeting this pathway has not been investigated. Here, we employed a small molecule inhibitor of NF-κB, DHMEQ (which mainly blocks nuclear translocation of activated NF-κB) and demonstrated significant inhibition of NPC cell proliferation, migration, invasion, as well as anchorage-independent growth. These antitumor effects were associated with induction of G₂/M cell cycle arrest and apoptosis, and downregulation of NF-κB target genes (EGFR, cyclin D1 and survivin). This first demonstration of therapeutic benefits of NF-κB targeting in NPC implicates the importance of targeting this pathway in NPC.     

Significance of VEGF and NF-κB Expression in Thyroid Carcinoma

Vascular endothelial growth factor (VEGF), a dimeric 42-kd pro- tein, is a multifunctional cytokine that plays a key role in both physiological and pathological angiogenesis.[1] Angiogenesis is known to be a prerequisite for tumor growth and metastasis.VE…     

NF-κB与结直肠癌

核因子κB（nuclear factor- κB, NF-κB）是一种重要的核转录因子,在调控细胞周期、凋亡和代谢等生理过程中发挥重要作用;然而,NF-κB在人类多种恶性肿瘤中过表达,在肿瘤的发生、发展和免疫炎症反应中也起着重要的调控作用。在结直肠癌中NF-κB同样呈高表达,且呈激活状态。NF-κB信号通路被激活后,NF-κB转入细胞核内,通过与下游靶基因结合,促进目的基因的转录,从而调控目的蛋白的表达,并介导多条信号通路,促进肿瘤细胞血管生成、增加肿瘤细胞增殖、抗凋亡和促进肿瘤细胞的侵袭、迁移和转移能力,以及对放化疗的抵抗,甚至诱导肿瘤细胞获得干性等恶性表型。研究表明,NF-κB过表达的结直肠癌患者病情进展较快,生存时间较短,NF-κB可作为结直肠癌患者疗效监测和预后监测的一个生物标志物,针对NF-κB及其信号通路的分子靶向治疗为结直肠癌患者治疗提供潜在的策略。     

NF-κB、IκB与肿瘤细胞凋亡

细胞核因子κＢ又称κ基因结合核因子(ｎｕｃｌｅａｒｆａｃｔｏｒκｇｅｎｅｂｉｎｄｉｎｇ,ＮＦκＢ),是1种广泛存在于细胞中的具有多向性调节作用的蛋白质分子,参与调控细胞激酶、趋化因子、生长因子、细胞粘附因子及早期反应的蛋白质分子基因的转录,其活性受到1个强抑制物ＩκＢ的抑制。近年来研究结果表明:ＮＦκＢ能介导广泛的生物学作用,参与多种疾病的发生发展过程。ＮＦκＢ在细胞凋亡中有一定的作用。1　ＮＦκＢ和ＩκＢＮＦκＢ是1种转录因子,有着广泛的生物学作用。1986年Ｓｅｎ等[1]最初发现ＮＦκＢ是1种与免疫球蛋白κ轻链…     

Finding a novel interacting protein of the hepatic carcinoma related gene MIP: NF-κB essential modulator (NEMO)

MafF interacting protein (MIP) is product of a candidate gene related to liver cancer development and progression. Here, we demonstrated that MIP could inhibit the proliferation of cancer cells through colony formation assays, and the inhibition ability of MIP to SMMC7721 cells was notably stronger than to HeLa cells. Using pGBKT7-MIP as bait, a human placenta cDNA library was screened using yeast two-hybrid system and a middle fragment of the NF-κB essential modulator (NEMO) was obtained as a novel important MIP interacting protein fragment, which contained 228 amino acid sequence from the 120 to 347 residue. Then the full coding sequence of NEMO was amplified from Clontech Placenta Marathon cDNA library and yeast mating assay verified the interaction of MIP and full length NEMO in yeast. GST pull-down assay and co-immunoprecipitation assay confirmed that MIP bound to NEMO specifically and directly. These results indicated that MIP interacted with NEMO and suggested that MIP could be involved in NF-κB signaling pathway, which is helpful to clarify the inhibition function of MIP to cancer cell proliferation.     

Curcumin Analog Pentagamavunon-1 (PGV-1) Sensitizes Widr Cells to 5-Fluorouracil through Inhibition of NF-κB Activation

Cell cycle regulation and the NF-κB pathway in cancer cells are important in mediating resistance to 5-Fluorouracil (5-FU). Pentagamavunon-1 (PGV-1), a curcumin analog, is known to exhibit stronger growth inhibitory effects than curcumin itself in several cancer cells. In this study, we evaluated the potency of PGV-1 in combination with 5-FU in WiDr colon cancer cells. In MTT assays, PGV-1 did not only exhibit stronger growth inhibitory effects than both 5-FU and curcumin, but also enhanced the cytotoxicity of 5-FU. Flow cytometry demonstrated that single treatments with PGV-1 and 5-FU resulted in different effects on cell cycle profiles. PGV-1 induced G2/M arrest while 5-FU caused S-phase arrest at low concentration (1 μM) and G1-phase arrest at high concentration (100 μM). Interestingly, the combination of 5-FU and PGV-1 enhanced cell accumulation in S-phase. Although a single treatment with either 5-FU or PGV-1 increased cyclin D1 at the protein level, the combination treatment resulted in significant suppression. In addition, PGV-1 inhibited activation of NF-κB and suppressed the expression of cyclooxygenase-2, an NF-κB downstream protein. In conclusion, PGV-1 increased the cytotoxic effect of 5-FU on WiDr cells through inhibition of NF-κB activation.     

NF-κB regulates the response of embryonic cells to heat shock

NF-κB was shown previously to regulate apoptotic cell death processes in various experimental systems. However, its role in controlling teratogen-induced cell death has not been established yet. Therefore, the objective of the present study was to explore the involvement of the p65 subunit of NF-κB in the response of mouse embryonic fibroblasts (MEFs) to heat shock, using p65 knockout (p65^?/?) cells. Indeed, we found p65^?/? MEFs to be more susceptible to the exposure to heat shock, as compared with wild-type (WT) MEFs, as they demonstrated a more prominent decrease in cell survival and proliferation as well as the appearance of cells undergoing apoptotic cell death. These heat-shock-induced effects were preceded by a decrease in p65 expression in WT cells, which was accompanied by a decrease in IκBα expression in WT MEFs, while disappearing completely in p65^?/? MEFs and accordingly, by an increase in p-IκBα expression in both cell lines, which was found to be more prominent in p65^?/? MEFs. Interestingly, the heat shock-induced decrease in p65 expression was accompanied by an increase in HSP70 expression in both cell lines. However, it was again found to be more prominent in p65^?/? MEFs. Taken together, our results suggest a protective role for the p65 subunit of NF-κB in mechanisms underlying the response of embryonic cells to heat shock.     

NF-κB in cancer: a matter of life and death

Activation of NF-κB has been linked to various cellular processes in cancer, including inflammation, transformation, proliferation, angiogenesis, invasion, metastasis, chemoresistance, and radioresistance. Although acute inflammation mediates innate and humoral immunity, chronic inflammation has been linked to tumorigenesis. Thus, inhibition of NF-κB has therapeutic potential in sensitization of tumors to chemotherapeutic agents; however, generalized suppression of NF-κB can result in serious host toxicity with minimum effect on the tumor.     

The diverse and complex roles of NF-κB subunits in cancer

It is only recently that the full importance of nuclear factor-κB (NF-κB) signalling to cancer development has been understood. Although much attention has focused on the upstream pathways leading to NF-κB activation, it is now becoming clear that the inhibitor of NF-κB kinases (IKKs), which regulate NF-κB activation, have many independent functions in tissue homeostasis and normal immune function that could compromise the clinical utility of IKK inhibitors. Therefore, if the NF-κB pathway is to be properly exploited as a target for both anticancer and anti-inflammatory drugs, it is appropriate to reconsider the complex roles of the individual NF-κB subunits.     

Antitumor effect of berberine against primary effusion lymphoma via inhibition of NF-κB pathway

Primary effusion lymphoma (PEL) is an infrequent and distinct entity among the aggressive non-Hodgkin B cell lymphomas that occurs predominantly in patients with advanced AIDS. It shows serous lymphomatous effusion in body cavities, and is resistant to conventional chemotherapy with a poor prognosis. Thus, the optimal treatment for PEL is not well defined and there is a need for novel agents. PEL has been recognized as the tumor caused by Kaposi sarcoma-associated herpes virus/human herpes virus-8 (KSHV/HHV-8), and nuclear factor (NF)-κB activation plays a critical role in the survival and growth of PEL cells. In this study, we assessed the antitumor effect of berberine, a naturally occurring isoquinoline alkaloid, on this pathway. The methylthiotetrazole assay showed that cell proliferation in the PEL cell lines was inhibited by berberine. Berberine also induced caspase-dependent apoptosis and suppressed NF-κB activity by inhibiting IκB kinase (IKK) phosphorylation, IκB phosphorylation and IκB degradation, upstream targets of the NF-κB pathway, in PEL cells. In a xenograft mouse model that showed ascites and diffuse organ invasion of PEL cells, treatment with berberine inhibited the growth and invasion of PEL cells significantly compared with untreated mice. These results show that the suppression of NF-κB is a molecular target for treating PEL, and berberine is a potential antitumor agent for PEL.     

Nickel chloride (NiCl2)-caused inflammatory responses via activation of NF-κB pathway and reduction of anti-inflammatory mediator expression in the kidney

Nickel (Ni) or Ni compounds target a number of organs and produce multiple toxic effects. Kidney is the major organ for Ni accumulation and excretion. There are no investigations on the Ni- or Ni compounds-induced renal inflammatory responses in human beings and animals at present. Therefore, we determined NiCl₂-caused alteration of inflammatory mediators, and functional damage in the broiler''s kidney by the methods of biochemistry, immunohistochemistry and quantitative real-time polymerase chain reaction (qRT-PCR). Dietary NiCl₂ in excess of 300 mg/kg caused the renal inflammatory responses that characterized by increasing mRNA expression levels of the pro-inflammatory mediators including tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8) and interleukin-18 (IL-18) via the activation of nucleic factor κB (NF-κB), and decreasing mRNA expression levels of the anti-inflammatory mediators including interleukin-2 (IL-2), interleukin-4 (IL-4) and interleukin-13 (IL-13). Concurrently, NiCl₂ caused degeneration, necrosis and apoptosis of the tubular cells, which was consistent with the alteration of renal function parameters including elevated alkaline phosphatase (AKP) activity, and reduced activities of sodium-potassium adenosine triphosphatase (Na⁺/K⁺-ATPase), calcium adenosine triphosphatase (Ca²⁺-ATPase), lactic dehydrogenase (LDH), succinate dehydrogenase (SDH) and acid phosphatase (ACP) in the kidney. The above-mentioned results present that the activation of NF-κB pathway and reduction of anti-inflammatory mediator expression are main mechanisms of NiCl2-caused renal inflammatory responses and that the renal function is decreased or impaired after NiCl2-treated.