Mol. Cells 2014; 37(3): 189-195
Published online March 3, 2014
https://doi.org/10.14348/molcells.2014.2353
© The Korean Society for Molecular and Cellular Biology
Correspondence to : *Correspondence: soyoung.lee@charite.de
The NF-κB pathway transcriptionally controls a large set of target genes that play important roles in cell survival, inflammation, and immune responses. While many studies showed anti-tumorigenic and pro-survival role of NF-κB in cancer cells, recent findings postulate that NF-κB participates in a senescence-associated cytokine response, thereby suggesting a tumor restraining role of NF-κB. In this review, we discuss implications of the NF-κB signaling pathway in cancer. Particularly, we emphasize the connection of NF-κB with cellular senescence as a response to chemotherapy, and furthermore, present examples how distinct oncogenic network contexts surrounding NF-κB produce fundamentally different treatment outcomes in aggressive B-cell lymphomas as an example.
Keywords cancer, chemotherapy, NF-κB, senescence
The nuclear factor κB (NF-κB) is a transcription factor complex composed of homo- and heterodimers of five members of the Rel family including RelA (p65), RelB, c-Rel, NF-κB1 (p50/p105), NF-κB2 (p52/p100). More than 25 years after it was first described as a nuclear protein binding to the kappa immunoglobulin light chain enhancer in B cells (Sen and Baltimore, 1986), NF-κB is now known to control a complex signaling network
Of the five NF-κB family members in mammalian cells, p105 and p100 are precursors, and, after post-translational modification and cleavage, become p50 and p52, respectively. They share a conserved Rel homology domain (RHD), which is responsible for binding to target DNA sequence, homo/heterodimerization, and the interaction with the inhibitor protein IκB. With each other, NF-κB family members form homo- or heterodimers, and in the absence of any stimulation (inactive state), also with IκB. Activation of the NF-κB signaling cascade can be divided into two pathways depending on how the active homo-/heterodimers are produced. In the classical (or canonical) pathway, activation is achieved by releasing IκB from the inactive complex
A wide range of stimuli, including inflammatory cytokines, bacterial and viral products, are known to activate the NF-κB pathway resulting in transcriptionally active NF-κB complexes as described above. The active complexes translocate into the nucleus and bind to discrete DNA sequences in promoters and enhancers of target genes to activate transcription. There are many NF-κB target genes, orchestrating a plethora of biological functions, including anti-apoptosis, cell adhesion, cellular stress responses, inflammation, and immunity (Hayden and Ghosh, 2008).
NF-κB activities are frequently deregulated in cancer, representing one of the most important signaling cascades in transformed cells with mainly proto-oncogenic impact (Perkins, 2007). Constitutive activation of NF-κB has been observed in different kinds of cancer, including lymphoma, leukemia, breast, colon, liver, pancreas, prostate, and ovarian cancers. Moreover, activation of NF-κB has often been linked to recurrence, poor survival, tumor progression, aggressiveness, and chemoresistance (Arkan and Greten, 2011; Basseres and Baldwin, 2006; Prasad et al., 2010). However, there are also studies that found NF-κB transcription factors or upstream activators rather to act as tumor suppressors. NF-κB controls the expression of a large set of target genes, including pro-survival and pro-inflammatory transcripts, but the actual role of NF-κB as a tumor suppressor or rather a tumor promoter, as well as it’s potential interference with treatment outcome is controversial (Ben-Neriah and Karin, 2011).
Since NF-κB is normally involved in B-cell maturation and activation, deregulation of the NF-κB pathway is a prominent feature of hematological malignancies. Mutations in genes encoding NF-κB subunits, IκB proteins, or upstream regulators were identified in a variety of hematological malignancies (Compagno et al., 2009; Franzoso et al., 1992; Neri et al., 1991). There are now a number of lymphoid malignancies known, where constitutive NF-κB has been implicated as an essential oncogenic lesion. Mutations of multiple genes in receptor complexes (e.g. CD79-ITAM and MyD88), signaling complexes (e.g. TNFAIP3 [A20], CARD11-BCL10-MALT1 [CBM]), and the core signaling complexes (e.g. IKK, c-Rel) cause deregulation of NF-κB pathway in human lymphomas (Ngo et al., 2011; Rosenwald et al., 2002; Sun et al., 2004; Zhou et al., 2004). A good example of NF-κB’s essential role in cancer development can be found in diffuse large B-cell lymphoma (DLBCL) which can be divided into at least two subtypes according to their gene-expression profiling: the activated B-cell-like (ABC) subtype and the germinal-center B-cell-like (GCB) subtype. The main signature of the ABC subtype is the constitutive activation of the NF-κB pathway, which is rarely hyperactivated in GCB-DLBCL. Activating mutations in CARD11 (which encodes Carma-1) have been detected in ABC DLBCL, generating constitutively active CARD11 that associates with the Bcl-10-MALT1 complex (CBM complex; mediates NF-κB signaling between antigen receptor and IKK) without antigenic stimulation, leading to persistent activation of NF-κB (Lenz et al., 2008a; Ngo et al., 2006; Staudt, 2010). A20 is a negative regulator of the NF-κB pathway, as it prevents excessive activation of NF-κB in response to a variety of external stimuli (Heyninck and Beyaert, 2005; Wertz et al., 2004). It is frequently inactivated by truncating mutations and/or deletions in B-cell lymphomas, further adding to the theme that uncontrolled signaling of NF-κB is involved in the pathogenesis of B-cell malignancies. In multiple myeloma, another lymphoid neoplasia associated with NF-κB activation, no mutations in NF-κB or IκB encoding genes have been unveiled so far but extensive genetic analysis of primary tumors and multiple myeloma cell lines discovered a number of mutations in genes encoding upstream signaling molecules that lead to stabilization and accumulation of the NF-κB inducing kinase (NIK) in non-canonical pathway (Annunziata et al., 2007; Keats et al., 2007).
Oncogenic mutations in NF-κB signal mediators appear to be rare in solid tumors. However, oncogenic signaling, for example from activated Ras, may enhance NF-κB activity in the absence of mutations. Moreover, inflammation-associated NF-κB-driven cytokine production promotes carcinogenesis in a non cell- autonomous fashion (Ben and Karin, 2011; Staudt, 2010). Accordingly, mouse models demonstrated an oncogenic role for NF-κB in the development of lymphomas and solid tumors (Basseres et al., 2010; Calado et al., 2010; Yang et al., 2010).
In addition, the number of tumors with activated nuclear NF-κB is much larger than the fraction of malignancies with confirmed mutations in NF-κB-, IκB-, or typical upstream signal mediator-encoding genes. Such observations led to the proposal that some of the NF-κB activation seen in cancer is due to crosstalk from other deregulated pathways that fuel into the NF-κB cascade or is the result of external stimuli such as exposure to inflammatory cytokines in the tumor microenvironment. Production of the cytokines by immune cells that activate the NF-κB pathway in pre-malignant cells to induce genes that stimulate cell proliferation and survival is a major tumor-promoting mechanism (Grivennikov et al., 2010). For example, TNFα and IL-1 secreted by the environmental cells were shown to act on premalignant cells where they activate NF-κB. NF-κB activation further induces expression of genes involved in blockade of apoptosis, promotion of proliferation and angiogenesis, mechanisms collectively contributing to malignant conversion (Popivanova et al., 2008; Tu et al., 2008).
Although NF-κB transcription factors have an oncogenic role in cancer development and confer drug resistance in cancer therapy in some settings, other studies found NF-κB transcription factors or upstream activators rather to act as tumor suppressors, thereby underscoring the complexity and potential context dependency of NF-κB network-mediated effector functions in both tumor development and therapy.
Contributing to its anti-cancer property, NF-κB has been shown to mediate apoptosis in a variety of cell types (Ryan et al., 2000; Wang et al., 1998). For instance, RelA and c-Rel exert proapoptotic function in T cells, B cells, fibroblasts, neuronal cells, and HeLa cells (Kaltschmidt et al., 2000; Kasibhatla et al., 1999; Martin et al., 2009; Schneider et al., 1999; Sheehy and Schlissel, 1999). There are also hints that NF-κB may modulate the apoptotic response depending on the developmental stage of the immune cells. For example, overexpression of RelA caused a cell-cycle arrest that is followed by apoptosis in the pro-B cell line 220?8, whereas overexpression of RelA in the WEHI 231 immature B-cell line or in the mature B-cell line M12 did not induce apoptosis (Sheehy and Schlissel, 1999).
Importantly, genetically defined mouse models supported the view that NF-κB transcription factors or upstream activators possess tumor suppressor functions. First evidence directly linking NF-κB to tumor suppression came from experiments using epidermal cells. Functional blockade of NF-κB in epidermal cells resulted in severe hyperplasia of the skin in transgenic mice expressing dominant negative IκBα mutant, which was reversible upon overexpression of active RelA and p50 subunits of NF-κB, suggesting a tumor-suppressive effect of NF-κB (Seitz et al., 1998). In a diethylnitrosamine-induced hepatocellular carcinoma (HCC) mouse model, hepatocyte-specific ablation of IKKβ strongly enhanced the development of HCC (Maeda et al., 2005). In other studies, hepatocyte-specific ablation of IKKγ (NEMO) or TAK1 (TGF-β-activated kinase 1), both required for the activation of IKK and NF-κB, resulted in spontaneous liver damage, hepatocyte death, and interestingly, release of factors leading to liver fibrosis and development of HCC (Inokuchi et al., 2010; Luedde et al., 2007). In the Eμ-myc transgenic mouse lymphoma model, in which oncogene Myc is overexpressed and drives B-cell lymphoma, NF-κB2 loss accelerated tumor development by impairing Myc’s apoptotic response, adding an example for a tumor suppressive function of NF-κB
Given the well-established overlap between failsafe barriers such as apoptosis and senescence in tumor development and therapy, the NF-κB pathway has also been linked to chemoresistance in cancer treatment. Activation of NF-κB occurs in response to DNA damage, the mode by which most conventional chemotherapeutic agents exert their anti-cancer activity. Among the NF-κB target genes activated by DNA damage are bcl-2 (Catz and Johnson, 2001), bcl-xL (Tamatani et al., 1999), COX-2 (Yamamoto et al., 1995), cyclin D1 (Guttridge et al., 1999), survivin (Zhu et al., 2001), and XIAP (Stehlik et al., 1998), which are closely involved in anti-apoptotic, pro-survival functions of NF-κB, thereby operating as candidate mediators of chemoresistance in a wide variety of tumor cells.
Since the downstream targets of NF-κB are involved in apoptosis inhibition and may thereby block the action of many forms of chemotherapy (Baldwin, 2001), it may also contribute to the poor response of the ABC DLBCL to chemotherapy (Alizadeh et al., 2000; Lenz et al., 2008b; Rosenwald et al., 2002). This hypothesis is supported by several
Premature cellular senescence is a terminal cell-cycle arrest that can be induced by oncogenic activation or chemotherapy, involving DNA damage response (DDR) signaling in both settings (Kuilman et al., 2010; Schmitt, 2007). It has been demonstrated that oncogene-induced senescence (OIS) imposes a critical barrier to tumor formation
Interestingly, recent publications postulated that senescence-associated and predominantly NF-κB-driven cytokines, collectively termed “senescence-associated secretory phenotype (SASP)”, may reinforce the senescent cell-cycle arrest (Acosta et al., 2008; Coppe et al., 2008; Kuilmann et al., 2008; Rovillain et al., 2011). These - on first sight - counter-intuitive, double-edged functions of NF-κB to promote both chemoresistance
The data described above highlight how oncogenic networks and interdependencies, wired up during tumor development, may regulate the actual functions and even opposing roles of NF-κB in subsequent responses to therapy. NF-κB and Bcl2 are generally considered as indicators of aggressive tumor biology and poor outcome, but our mechanistic analyses in a genetically tractable mouse lymphoma model unveiled a setting in which these moieties contribute to superior outcome. Our approach demonstrates that functional understanding of oncogenic networks - and NF-κB/Bcl2 forms the most simple model of such a “two-factor network” with a linear connection in one (ABC-type), but an independent role of both factors in the other setting (GCB-type) - is required to properly utilize molecular lesions as biomarkers or even therapeutic targets (Fig. 2).
The SASP is composed of pro-inflammatory cytokines such as IL-1α, IL-1β, IL-6, IL-8, bFGF, TGF-β (in some settings), GMCSF, as well as inflammation-related chemokines such as CXCL-1/-2/-3/-5/-7, MIP-1α, or MCP-1 (a.k.a. CCL2). It also contains factors with, at least in some contexts, anti-proliferative activity such as IGFBPs or PAI-1, as well as factors like the MMPs that remodel the extracellular matrix (Acosta et al., 2008; Kortlever et al., 2006; Kuilman and Peeper, 2009). Moreover, in an extend view on the SASP program as a senescence-associated pro-inflammatory signaling array, this phenotype is not restricted to secreted factors, but also includes membrane-bound cell surface molecules serving as ligands and receptors, for instance TNF receptors, CXCR2 or the IL-6R, thereby creating potential autocrine loops (e.g. CXCL-1/-5/-7 or IL-8 with CXCR2) or even, as reported, intra-cellular short cuts (e.g. IL-6 and the IL-6R), and self-amplifying cascades (e.g. NF-κB signaling
Therefore, the expression of surface-presented receptors and ligands and the secretion of a plethora of factors by senescent cancer cells may have complex, growth-inhibitory or -promoting effects on adjacent tumor and surrounding bystander cells. In particular, factors secreted by senescent cells can also act on macrophages, neutrophils, and NK cells, thereby promoting immune responses that, on one hand, may ultimately lead to the clearance of senescent tumor cells (Xue et al., 2007), but, on the other hand, might also create a microenvironment that fosters tumor progression (Copp? et al., 2010). Given our own observation that macrophage-derived TGFb evokes lymphoma cell senescence in a non-cell-autonomous fashion (Reimann et al., 2010), SASP-activated macrophages are likely to contribute to TIS
Chemotherapy is still the most important treatment method for many types of cancer. The possible outcomes of chemotherapeutic treatments reach from necrosis, apoptosis, mitotic catastrophe, and autophagy to cellular senescence. Most of the chemotherapeutic agents used in the clinic are assumed to exert their anti-tumor effect through the induction of apoptosis. Accordingly, cancer cells with apoptotic defects would exhibit chemoresistance. As an example, ABC-subtype DLBCL present with an inferior prognosis after chemotherapy, and are characterized by constitutive activation of the NF-κB pathway, which appears to confer treatment resistance
Mol. Cells 2014; 37(3): 189-195
Published online March 31, 2014 https://doi.org/10.14348/molcells.2014.2353
Copyright © The Korean Society for Molecular and Cellular Biology.
Hua Jing1,2, and Soyoung Lee1,*
1MKFZ, Charit? ? Universit?tsmedizin Berlin and Max-Delbr?ck-Centrum for Molecular Medicine, Berlin, Germany, 2Present address: Department of Radiation Oncology, University Hospital Freiburg, Freiburg, Germany
Correspondence to:*Correspondence: soyoung.lee@charite.de
The NF-κB pathway transcriptionally controls a large set of target genes that play important roles in cell survival, inflammation, and immune responses. While many studies showed anti-tumorigenic and pro-survival role of NF-κB in cancer cells, recent findings postulate that NF-κB participates in a senescence-associated cytokine response, thereby suggesting a tumor restraining role of NF-κB. In this review, we discuss implications of the NF-κB signaling pathway in cancer. Particularly, we emphasize the connection of NF-κB with cellular senescence as a response to chemotherapy, and furthermore, present examples how distinct oncogenic network contexts surrounding NF-κB produce fundamentally different treatment outcomes in aggressive B-cell lymphomas as an example.
Keywords: cancer, chemotherapy, NF-κB, senescence
The nuclear factor κB (NF-κB) is a transcription factor complex composed of homo- and heterodimers of five members of the Rel family including RelA (p65), RelB, c-Rel, NF-κB1 (p50/p105), NF-κB2 (p52/p100). More than 25 years after it was first described as a nuclear protein binding to the kappa immunoglobulin light chain enhancer in B cells (Sen and Baltimore, 1986), NF-κB is now known to control a complex signaling network
Of the five NF-κB family members in mammalian cells, p105 and p100 are precursors, and, after post-translational modification and cleavage, become p50 and p52, respectively. They share a conserved Rel homology domain (RHD), which is responsible for binding to target DNA sequence, homo/heterodimerization, and the interaction with the inhibitor protein IκB. With each other, NF-κB family members form homo- or heterodimers, and in the absence of any stimulation (inactive state), also with IκB. Activation of the NF-κB signaling cascade can be divided into two pathways depending on how the active homo-/heterodimers are produced. In the classical (or canonical) pathway, activation is achieved by releasing IκB from the inactive complex
A wide range of stimuli, including inflammatory cytokines, bacterial and viral products, are known to activate the NF-κB pathway resulting in transcriptionally active NF-κB complexes as described above. The active complexes translocate into the nucleus and bind to discrete DNA sequences in promoters and enhancers of target genes to activate transcription. There are many NF-κB target genes, orchestrating a plethora of biological functions, including anti-apoptosis, cell adhesion, cellular stress responses, inflammation, and immunity (Hayden and Ghosh, 2008).
NF-κB activities are frequently deregulated in cancer, representing one of the most important signaling cascades in transformed cells with mainly proto-oncogenic impact (Perkins, 2007). Constitutive activation of NF-κB has been observed in different kinds of cancer, including lymphoma, leukemia, breast, colon, liver, pancreas, prostate, and ovarian cancers. Moreover, activation of NF-κB has often been linked to recurrence, poor survival, tumor progression, aggressiveness, and chemoresistance (Arkan and Greten, 2011; Basseres and Baldwin, 2006; Prasad et al., 2010). However, there are also studies that found NF-κB transcription factors or upstream activators rather to act as tumor suppressors. NF-κB controls the expression of a large set of target genes, including pro-survival and pro-inflammatory transcripts, but the actual role of NF-κB as a tumor suppressor or rather a tumor promoter, as well as it’s potential interference with treatment outcome is controversial (Ben-Neriah and Karin, 2011).
Since NF-κB is normally involved in B-cell maturation and activation, deregulation of the NF-κB pathway is a prominent feature of hematological malignancies. Mutations in genes encoding NF-κB subunits, IκB proteins, or upstream regulators were identified in a variety of hematological malignancies (Compagno et al., 2009; Franzoso et al., 1992; Neri et al., 1991). There are now a number of lymphoid malignancies known, where constitutive NF-κB has been implicated as an essential oncogenic lesion. Mutations of multiple genes in receptor complexes (e.g. CD79-ITAM and MyD88), signaling complexes (e.g. TNFAIP3 [A20], CARD11-BCL10-MALT1 [CBM]), and the core signaling complexes (e.g. IKK, c-Rel) cause deregulation of NF-κB pathway in human lymphomas (Ngo et al., 2011; Rosenwald et al., 2002; Sun et al., 2004; Zhou et al., 2004). A good example of NF-κB’s essential role in cancer development can be found in diffuse large B-cell lymphoma (DLBCL) which can be divided into at least two subtypes according to their gene-expression profiling: the activated B-cell-like (ABC) subtype and the germinal-center B-cell-like (GCB) subtype. The main signature of the ABC subtype is the constitutive activation of the NF-κB pathway, which is rarely hyperactivated in GCB-DLBCL. Activating mutations in CARD11 (which encodes Carma-1) have been detected in ABC DLBCL, generating constitutively active CARD11 that associates with the Bcl-10-MALT1 complex (CBM complex; mediates NF-κB signaling between antigen receptor and IKK) without antigenic stimulation, leading to persistent activation of NF-κB (Lenz et al., 2008a; Ngo et al., 2006; Staudt, 2010). A20 is a negative regulator of the NF-κB pathway, as it prevents excessive activation of NF-κB in response to a variety of external stimuli (Heyninck and Beyaert, 2005; Wertz et al., 2004). It is frequently inactivated by truncating mutations and/or deletions in B-cell lymphomas, further adding to the theme that uncontrolled signaling of NF-κB is involved in the pathogenesis of B-cell malignancies. In multiple myeloma, another lymphoid neoplasia associated with NF-κB activation, no mutations in NF-κB or IκB encoding genes have been unveiled so far but extensive genetic analysis of primary tumors and multiple myeloma cell lines discovered a number of mutations in genes encoding upstream signaling molecules that lead to stabilization and accumulation of the NF-κB inducing kinase (NIK) in non-canonical pathway (Annunziata et al., 2007; Keats et al., 2007).
Oncogenic mutations in NF-κB signal mediators appear to be rare in solid tumors. However, oncogenic signaling, for example from activated Ras, may enhance NF-κB activity in the absence of mutations. Moreover, inflammation-associated NF-κB-driven cytokine production promotes carcinogenesis in a non cell- autonomous fashion (Ben and Karin, 2011; Staudt, 2010). Accordingly, mouse models demonstrated an oncogenic role for NF-κB in the development of lymphomas and solid tumors (Basseres et al., 2010; Calado et al., 2010; Yang et al., 2010).
In addition, the number of tumors with activated nuclear NF-κB is much larger than the fraction of malignancies with confirmed mutations in NF-κB-, IκB-, or typical upstream signal mediator-encoding genes. Such observations led to the proposal that some of the NF-κB activation seen in cancer is due to crosstalk from other deregulated pathways that fuel into the NF-κB cascade or is the result of external stimuli such as exposure to inflammatory cytokines in the tumor microenvironment. Production of the cytokines by immune cells that activate the NF-κB pathway in pre-malignant cells to induce genes that stimulate cell proliferation and survival is a major tumor-promoting mechanism (Grivennikov et al., 2010). For example, TNFα and IL-1 secreted by the environmental cells were shown to act on premalignant cells where they activate NF-κB. NF-κB activation further induces expression of genes involved in blockade of apoptosis, promotion of proliferation and angiogenesis, mechanisms collectively contributing to malignant conversion (Popivanova et al., 2008; Tu et al., 2008).
Although NF-κB transcription factors have an oncogenic role in cancer development and confer drug resistance in cancer therapy in some settings, other studies found NF-κB transcription factors or upstream activators rather to act as tumor suppressors, thereby underscoring the complexity and potential context dependency of NF-κB network-mediated effector functions in both tumor development and therapy.
Contributing to its anti-cancer property, NF-κB has been shown to mediate apoptosis in a variety of cell types (Ryan et al., 2000; Wang et al., 1998). For instance, RelA and c-Rel exert proapoptotic function in T cells, B cells, fibroblasts, neuronal cells, and HeLa cells (Kaltschmidt et al., 2000; Kasibhatla et al., 1999; Martin et al., 2009; Schneider et al., 1999; Sheehy and Schlissel, 1999). There are also hints that NF-κB may modulate the apoptotic response depending on the developmental stage of the immune cells. For example, overexpression of RelA caused a cell-cycle arrest that is followed by apoptosis in the pro-B cell line 220?8, whereas overexpression of RelA in the WEHI 231 immature B-cell line or in the mature B-cell line M12 did not induce apoptosis (Sheehy and Schlissel, 1999).
Importantly, genetically defined mouse models supported the view that NF-κB transcription factors or upstream activators possess tumor suppressor functions. First evidence directly linking NF-κB to tumor suppression came from experiments using epidermal cells. Functional blockade of NF-κB in epidermal cells resulted in severe hyperplasia of the skin in transgenic mice expressing dominant negative IκBα mutant, which was reversible upon overexpression of active RelA and p50 subunits of NF-κB, suggesting a tumor-suppressive effect of NF-κB (Seitz et al., 1998). In a diethylnitrosamine-induced hepatocellular carcinoma (HCC) mouse model, hepatocyte-specific ablation of IKKβ strongly enhanced the development of HCC (Maeda et al., 2005). In other studies, hepatocyte-specific ablation of IKKγ (NEMO) or TAK1 (TGF-β-activated kinase 1), both required for the activation of IKK and NF-κB, resulted in spontaneous liver damage, hepatocyte death, and interestingly, release of factors leading to liver fibrosis and development of HCC (Inokuchi et al., 2010; Luedde et al., 2007). In the Eμ-myc transgenic mouse lymphoma model, in which oncogene Myc is overexpressed and drives B-cell lymphoma, NF-κB2 loss accelerated tumor development by impairing Myc’s apoptotic response, adding an example for a tumor suppressive function of NF-κB
Given the well-established overlap between failsafe barriers such as apoptosis and senescence in tumor development and therapy, the NF-κB pathway has also been linked to chemoresistance in cancer treatment. Activation of NF-κB occurs in response to DNA damage, the mode by which most conventional chemotherapeutic agents exert their anti-cancer activity. Among the NF-κB target genes activated by DNA damage are bcl-2 (Catz and Johnson, 2001), bcl-xL (Tamatani et al., 1999), COX-2 (Yamamoto et al., 1995), cyclin D1 (Guttridge et al., 1999), survivin (Zhu et al., 2001), and XIAP (Stehlik et al., 1998), which are closely involved in anti-apoptotic, pro-survival functions of NF-κB, thereby operating as candidate mediators of chemoresistance in a wide variety of tumor cells.
Since the downstream targets of NF-κB are involved in apoptosis inhibition and may thereby block the action of many forms of chemotherapy (Baldwin, 2001), it may also contribute to the poor response of the ABC DLBCL to chemotherapy (Alizadeh et al., 2000; Lenz et al., 2008b; Rosenwald et al., 2002). This hypothesis is supported by several
Premature cellular senescence is a terminal cell-cycle arrest that can be induced by oncogenic activation or chemotherapy, involving DNA damage response (DDR) signaling in both settings (Kuilman et al., 2010; Schmitt, 2007). It has been demonstrated that oncogene-induced senescence (OIS) imposes a critical barrier to tumor formation
Interestingly, recent publications postulated that senescence-associated and predominantly NF-κB-driven cytokines, collectively termed “senescence-associated secretory phenotype (SASP)”, may reinforce the senescent cell-cycle arrest (Acosta et al., 2008; Coppe et al., 2008; Kuilmann et al., 2008; Rovillain et al., 2011). These - on first sight - counter-intuitive, double-edged functions of NF-κB to promote both chemoresistance
The data described above highlight how oncogenic networks and interdependencies, wired up during tumor development, may regulate the actual functions and even opposing roles of NF-κB in subsequent responses to therapy. NF-κB and Bcl2 are generally considered as indicators of aggressive tumor biology and poor outcome, but our mechanistic analyses in a genetically tractable mouse lymphoma model unveiled a setting in which these moieties contribute to superior outcome. Our approach demonstrates that functional understanding of oncogenic networks - and NF-κB/Bcl2 forms the most simple model of such a “two-factor network” with a linear connection in one (ABC-type), but an independent role of both factors in the other setting (GCB-type) - is required to properly utilize molecular lesions as biomarkers or even therapeutic targets (Fig. 2).
The SASP is composed of pro-inflammatory cytokines such as IL-1α, IL-1β, IL-6, IL-8, bFGF, TGF-β (in some settings), GMCSF, as well as inflammation-related chemokines such as CXCL-1/-2/-3/-5/-7, MIP-1α, or MCP-1 (a.k.a. CCL2). It also contains factors with, at least in some contexts, anti-proliferative activity such as IGFBPs or PAI-1, as well as factors like the MMPs that remodel the extracellular matrix (Acosta et al., 2008; Kortlever et al., 2006; Kuilman and Peeper, 2009). Moreover, in an extend view on the SASP program as a senescence-associated pro-inflammatory signaling array, this phenotype is not restricted to secreted factors, but also includes membrane-bound cell surface molecules serving as ligands and receptors, for instance TNF receptors, CXCR2 or the IL-6R, thereby creating potential autocrine loops (e.g. CXCL-1/-5/-7 or IL-8 with CXCR2) or even, as reported, intra-cellular short cuts (e.g. IL-6 and the IL-6R), and self-amplifying cascades (e.g. NF-κB signaling
Therefore, the expression of surface-presented receptors and ligands and the secretion of a plethora of factors by senescent cancer cells may have complex, growth-inhibitory or -promoting effects on adjacent tumor and surrounding bystander cells. In particular, factors secreted by senescent cells can also act on macrophages, neutrophils, and NK cells, thereby promoting immune responses that, on one hand, may ultimately lead to the clearance of senescent tumor cells (Xue et al., 2007), but, on the other hand, might also create a microenvironment that fosters tumor progression (Copp? et al., 2010). Given our own observation that macrophage-derived TGFb evokes lymphoma cell senescence in a non-cell-autonomous fashion (Reimann et al., 2010), SASP-activated macrophages are likely to contribute to TIS
Chemotherapy is still the most important treatment method for many types of cancer. The possible outcomes of chemotherapeutic treatments reach from necrosis, apoptosis, mitotic catastrophe, and autophagy to cellular senescence. Most of the chemotherapeutic agents used in the clinic are assumed to exert their anti-tumor effect through the induction of apoptosis. Accordingly, cancer cells with apoptotic defects would exhibit chemoresistance. As an example, ABC-subtype DLBCL present with an inferior prognosis after chemotherapy, and are characterized by constitutive activation of the NF-κB pathway, which appears to confer treatment resistance
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