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TNF-alpha/NF-kappaB/Snail pathway in cancer cell migration and invasion.

Wu Y, Zhou BP - Br. J. Cancer (2010)

Bottom Line: A wide variety of evidence has pointed to a critical role of TNF-alpha in tumour proliferation, migration, invasion and angiogenesis.We will emphasise the contribution of TNF-alpha and the nuclear factor-kappaB pathway on tumour cell invasion and metastasis.Understanding the mechanisms underlying inflammation-mediated metastasis will reveal new therapeutic targets for cancer prevention and treatment.

View Article: PubMed Central - PubMed

Affiliation: Departments of Molecular and Biomedical Pharmacology, University of Kentucky School of Medicine, Lexington, 40506, USA.

ABSTRACT
Tumour necrosis factor-alpha (TNF-alpha) is an important inflammatory factor that acts as a master switch in establishing an intricate link between inflammation and cancer. A wide variety of evidence has pointed to a critical role of TNF-alpha in tumour proliferation, migration, invasion and angiogenesis. The function of TNF-alpha as a key regulator of the tumour microenvironment is well recognised. We will emphasise the contribution of TNF-alpha and the nuclear factor-kappaB pathway on tumour cell invasion and metastasis. Understanding the mechanisms underlying inflammation-mediated metastasis will reveal new therapeutic targets for cancer prevention and treatment.

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Related in: MedlinePlus

The downstream signalling pathways of TNF-α. The TNF-α can activate different pathways to induce apoptosis, cell survival or inflammation. Tumour necrosis factor induces the apoptosis by binding caspase-8 to FADD and promotes inflammation and survival, which is mediated through TRAF2 via JNK-dependent kinase cascade, MEKK kinase cascade and NF-κB activation by RIP.
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fig1: The downstream signalling pathways of TNF-α. The TNF-α can activate different pathways to induce apoptosis, cell survival or inflammation. Tumour necrosis factor induces the apoptosis by binding caspase-8 to FADD and promotes inflammation and survival, which is mediated through TRAF2 via JNK-dependent kinase cascade, MEKK kinase cascade and NF-κB activation by RIP.

Mentions: Tumour necrosis factor-α secretion can be induced by conserved structural elements common to microbial pathogens, such as lipopolysaccharide (LPS), that are bound by Toll-like receptors (TLRs) (Aderem and Ulevitch, 2000). The TLRs transcriptionally induce proinflammatory cytokines, including TNF-α, through the convergence of the nuclear factor (NF)-κB and NF-AT signalling pathways, and thereby enhance translational efficiency by a mechanism targeting consensus 3′-untranslated AU-rich elements (ARE) in mRNA (Dumitru et al, 2000). Tumour necrosis factor-α mediates its effect through two different receptors: TNF-α receptor I (TNF-R1; p55 or p60) and TNF-α receptor II (TNF-R2; p75 or p80) (Aggarwal, 2003). The TNF-R1 and TNF-R2 belong to the TNF super family receptors that have structurally related cysteine-rich extracellular domain. The TNF-R2 is expressed only on endothelial and immune cells. Although TNF-R2 has been shown to mediate signals that promote tissue repair and angiogenesis, the functional consequences of TNF-R2 signalling are not well characterised. The TNF-R1 is universally expressed on all cell types and has a broader role in NF-κB activation versus that of TNF-R2. The TNF-R1 ligation induces receptor trimerisation and the recruitment of the adaptor protein TNF-R1-associated death domain protein (TRADD) that binds to a specific death domain (DD) in the cytoplasmic domain of TNF-R1. TNF-R1-associated death domain protein also recruits TNF receptor-associated factor (TRAF2) and activates IκB kinase (IKK) through receptor-interacting protein (RIP). The RIP1 is ubiquitinated in a TRAF2-dependent manner during TNF-R1 activation and is essential for TNF-α-induced IKK and NF-κB activation. RIP1 knock-out cells fail to activate IKK in response to TNF-α. The TRAF2 recruits the IKK complex to the activated TNF-R1 by interacting with the LZ motifs of IKKα and IKKβ. The IKK complex consists of IKKα, IKKβ and NEMO (also known as IKKγ). In the classical activation pathway, activated IKKβ phosphorylates specific serine residues of IκB in a NEMO-dependent manner, leading to IκB phosphorylation, ubiquitination and proteosome-mediated degradation. The degradation of IκB releases the transcription factors NF-κB, which translocates to the nucleus, binds the κB site and activates gene transcription. Nuclear factor-κB is composed of five distinct but structurally related subunits, p50, p52, c-Rel, RelA and RelB. These subunits can form various homodimeric and heterdimeric complexes; each combination of subunits has a specific signalling function (Ghosh et al, 1998). These subunits are transcriptionally inactive when they form complexes with cytoplasmic IκB family proteins. Ligation of TNF-R1 is both necessary and sufficient to induce the cytotoxic and proinflammatory TNF-α response. The TNF-R2 may contribute to TNF-R1 responses at low concentrations of TNF-α, in which TNF-R2 captures TNF-α and passes it to TNF-R1 (Bradley, 2008). Although the TNF-α signal transduction pathway is complex (Figure 1) and not fully understood, the pro-inflammatory effects of TNF-α are primarily because of its ability to activate NF-κB whereas the anti-tumor effects are due to activation of Caspase 3 and induction of apoptosis. In almost all cell types, when exposed to TNF-α, NF-κB is activated and leads to the expression of a variety of inflammation-related genes. Transient activation of NF-κB in response to stimulation by cytokines induces the inflammatory response; however, sustained activation of NF-κB has been associated with several aspects of oncogenesis, such as promoting cancer-cell proliferation, preventing apoptosis in drug resistance and increasing tumour angiogenesis and metastasis.


TNF-alpha/NF-kappaB/Snail pathway in cancer cell migration and invasion.

Wu Y, Zhou BP - Br. J. Cancer (2010)

The downstream signalling pathways of TNF-α. The TNF-α can activate different pathways to induce apoptosis, cell survival or inflammation. Tumour necrosis factor induces the apoptosis by binding caspase-8 to FADD and promotes inflammation and survival, which is mediated through TRAF2 via JNK-dependent kinase cascade, MEKK kinase cascade and NF-κB activation by RIP.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2837572&req=5

fig1: The downstream signalling pathways of TNF-α. The TNF-α can activate different pathways to induce apoptosis, cell survival or inflammation. Tumour necrosis factor induces the apoptosis by binding caspase-8 to FADD and promotes inflammation and survival, which is mediated through TRAF2 via JNK-dependent kinase cascade, MEKK kinase cascade and NF-κB activation by RIP.
Mentions: Tumour necrosis factor-α secretion can be induced by conserved structural elements common to microbial pathogens, such as lipopolysaccharide (LPS), that are bound by Toll-like receptors (TLRs) (Aderem and Ulevitch, 2000). The TLRs transcriptionally induce proinflammatory cytokines, including TNF-α, through the convergence of the nuclear factor (NF)-κB and NF-AT signalling pathways, and thereby enhance translational efficiency by a mechanism targeting consensus 3′-untranslated AU-rich elements (ARE) in mRNA (Dumitru et al, 2000). Tumour necrosis factor-α mediates its effect through two different receptors: TNF-α receptor I (TNF-R1; p55 or p60) and TNF-α receptor II (TNF-R2; p75 or p80) (Aggarwal, 2003). The TNF-R1 and TNF-R2 belong to the TNF super family receptors that have structurally related cysteine-rich extracellular domain. The TNF-R2 is expressed only on endothelial and immune cells. Although TNF-R2 has been shown to mediate signals that promote tissue repair and angiogenesis, the functional consequences of TNF-R2 signalling are not well characterised. The TNF-R1 is universally expressed on all cell types and has a broader role in NF-κB activation versus that of TNF-R2. The TNF-R1 ligation induces receptor trimerisation and the recruitment of the adaptor protein TNF-R1-associated death domain protein (TRADD) that binds to a specific death domain (DD) in the cytoplasmic domain of TNF-R1. TNF-R1-associated death domain protein also recruits TNF receptor-associated factor (TRAF2) and activates IκB kinase (IKK) through receptor-interacting protein (RIP). The RIP1 is ubiquitinated in a TRAF2-dependent manner during TNF-R1 activation and is essential for TNF-α-induced IKK and NF-κB activation. RIP1 knock-out cells fail to activate IKK in response to TNF-α. The TRAF2 recruits the IKK complex to the activated TNF-R1 by interacting with the LZ motifs of IKKα and IKKβ. The IKK complex consists of IKKα, IKKβ and NEMO (also known as IKKγ). In the classical activation pathway, activated IKKβ phosphorylates specific serine residues of IκB in a NEMO-dependent manner, leading to IκB phosphorylation, ubiquitination and proteosome-mediated degradation. The degradation of IκB releases the transcription factors NF-κB, which translocates to the nucleus, binds the κB site and activates gene transcription. Nuclear factor-κB is composed of five distinct but structurally related subunits, p50, p52, c-Rel, RelA and RelB. These subunits can form various homodimeric and heterdimeric complexes; each combination of subunits has a specific signalling function (Ghosh et al, 1998). These subunits are transcriptionally inactive when they form complexes with cytoplasmic IκB family proteins. Ligation of TNF-R1 is both necessary and sufficient to induce the cytotoxic and proinflammatory TNF-α response. The TNF-R2 may contribute to TNF-R1 responses at low concentrations of TNF-α, in which TNF-R2 captures TNF-α and passes it to TNF-R1 (Bradley, 2008). Although the TNF-α signal transduction pathway is complex (Figure 1) and not fully understood, the pro-inflammatory effects of TNF-α are primarily because of its ability to activate NF-κB whereas the anti-tumor effects are due to activation of Caspase 3 and induction of apoptosis. In almost all cell types, when exposed to TNF-α, NF-κB is activated and leads to the expression of a variety of inflammation-related genes. Transient activation of NF-κB in response to stimulation by cytokines induces the inflammatory response; however, sustained activation of NF-κB has been associated with several aspects of oncogenesis, such as promoting cancer-cell proliferation, preventing apoptosis in drug resistance and increasing tumour angiogenesis and metastasis.

Bottom Line: A wide variety of evidence has pointed to a critical role of TNF-alpha in tumour proliferation, migration, invasion and angiogenesis.We will emphasise the contribution of TNF-alpha and the nuclear factor-kappaB pathway on tumour cell invasion and metastasis.Understanding the mechanisms underlying inflammation-mediated metastasis will reveal new therapeutic targets for cancer prevention and treatment.

View Article: PubMed Central - PubMed

Affiliation: Departments of Molecular and Biomedical Pharmacology, University of Kentucky School of Medicine, Lexington, 40506, USA.

ABSTRACT
Tumour necrosis factor-alpha (TNF-alpha) is an important inflammatory factor that acts as a master switch in establishing an intricate link between inflammation and cancer. A wide variety of evidence has pointed to a critical role of TNF-alpha in tumour proliferation, migration, invasion and angiogenesis. The function of TNF-alpha as a key regulator of the tumour microenvironment is well recognised. We will emphasise the contribution of TNF-alpha and the nuclear factor-kappaB pathway on tumour cell invasion and metastasis. Understanding the mechanisms underlying inflammation-mediated metastasis will reveal new therapeutic targets for cancer prevention and treatment.

Show MeSH
Related in: MedlinePlus