NF-κΒ AND MITOCHONDRIA CROSS PATHS IN CANCER: MITOCHONDRIAL METABOLISM AND BEYOND

 

 

 

Daria Capecea, Daniela Verzellaa, Barbara Di Francescob, Edoardo Alesseb, Guido Franzosoa and Francesca Zazzeronib*

a Centre for Cell Signalling and Inflammation, Department of Medicine, Imperial College London, London W12 0NN, UK 

b Department of Biotechnological and Applied Clinical Sciences (DISCAB), University of L’Aquila, 67100 L’Aquila, Italy

 

*corresponding author

e-mail francesca.zazzeroni@univaq.it

full postal address: Department of Biotechnological and Applied Clinical Sciences (DISCAB), Via Vetoio 10 – Coppito II, 67100 L’Aquila, Italy

 

e-mail addresses:

 

Daria Capece: d.capece@imperial.ac.uk

Daniela Verzella: d.verzella@imperial.ac.uk

Barbara Di Francesco: barbara.difrancesco1@graduate.univaq.it

Edoardo Alesse: edoardo.alesse@univaq.it

Guido Franzoso: g.franzoso@ imperial.ac.uk

Francesca Zazzeroni: francesca.zazzeroni@univaq.it

 

 

 

 

 

 

 

 

 

 

 

 

ABSTRACT

NF-κB plays a pivotal role in oncogenesis. This transcription factor is best known for promoting cancer cell survival and tumour-driving inflammation. However, several lines of evidence support a crucial role for NF-κB in governing energy homeostasis and mediating cancer metabolic reprogramming. Mitochondria are central players in many metabolic processes altered in cancer. Beyond their bioenergetic activity, several facets of mitochondria biology, including mitochondrial dynamics and oxidative stress, promote and sustain malignant transformation. Recent reports revealed an intimate connection between NF-κB pathway and the oncogenic mitochondrial functions. NF-κΒ can impact mitochondrial respiration and mitochondrial dynamics, and, reciprocally, mitochondria can sense stress signals and convert them into cell biological responses leading to NF-κΒ activation. In this review we discuss their emerging reciprocal regulation and the significance of this interplay for anticancer therapy.

HIGHLIGHTS

· NF-κB governs energy homeostasis and promotes metabolic adaptation of cancer cells.

· Metabolic alteration and mitochondria have been recognised as key players in cancer.

· The interplay between NF-κΒ and mitochondria sustain oncogenesis.

KEYWORDS: NF-κB, mitochondria, OXPHOS, revers Warburg effect, ROS

INDEX

 

1. Introduction

2. Mitochondria and Cancer

2.1 Mitochondrial metabolism

2.2 Mitochondrial dynamics

2.3 Oxidative stress

3. NF-κΒ and Mitochondria in cancer

3.1 NF-κΒ bioenergetic functions

3.2 NF-κΒ role in the reverse Warburg effect

3.3 NF-κΒ, ROS and mitochondrial dynamics

4. Targeting opportunities

4.1 Targeting metabolic processes

4.2 The therapeutic challenge of targeting NF-κΒ

5. Concluding remarks and Future Perspective

Acknowledgments

Competing Financial Interests

References

1. Introduction

Constitutive activation of NF-κB transcription factors is frequently observed in many cancers and NF-κB transcriptional programs sustain most of the cancer’s hallmark [1–4]. Beyond fuelling tumour progression, metastatic dissemination and therapy resistance by regulating genes that suppress cancer-cell apoptosis and orchestrate inflammation in the tumour microenvironment (TME), NF-κB has been recently implicated in cancer cell metabolism [4–10].

In mammals, the NF-κB family of transcription factors consist of five highly conserved proteins, named RelA/p65, RelB, c-Rel, NF-κB1(p105/p50) and NF-κB2 (p100/p52). The active DNA-binding forms of NF-κB are homo- and heterodimeric complexes composed of various combinations of the NF-κB family members, the most represented of which is p50/p65 [11]. In resting cells, NF-κB dimers are sequestered in the cytoplasm by inhibitory proteins of the IκB family. The key molecular event driving NF-κB activation is the degradation of its inhibitors [12]. In the classical (or canonical) pathway, the IκB kinase (IKK) complex, formed by IKKα, IKKβ and IKKγ (NF-κB Essential Modulator, NEMO) phosphorylates IκBα, resulting in IκBα poly-ubiquitination and proteasomal degradation. The removal of the inhibitor allows NF-κB dimers to translocate into the nucleus and activate the transcription of target genes. The alternative (or noncanonical) pathway of NF-κB activation depends on NIK-depend activation of IKKα, which phosphorylates the p100 subunit of the complex p100-RelB, leading to the cleavage of p100 into p52, and the activation of p52-RelB dimers [12].

Historically, the metabolic phenotype of cancer cells has been associated to high glycolytic flux and defective mitochondrial respiration. This view mainly stems from the seminal observation made in 1920 by Otto Warburg that even in aerobic conditions tumour cells exhibited high glucose consumption and lactate production, a phenomenon referred as “aerobic glycolysis“ or “Warburg effect” [13]. Two main conclusions were drawn based on this observation. First, that glycolysis was the major pathway used by cancer cells to sustain rapid proliferation, and second, that tumours displayed dysfunctional mitochondria. The view that defective mitochondrial metabolism was a hallmark of cancer has been challenged by an increasing body of evidence suggesting that oxidative phosphorylation (OXPHOS) was not impaired in malignant cells, but even that mitochondria play an essential role in tumorigenesis [14–20], so much so that recent evidence point to them as a target for cancer therapy [21–23].

Mitochondria govern a plethora of fundamental cellular functions, beyond bioenergetics, including biosynthetic metabolism, redox homeostasis and cell signalling. This complex of roles makes these organelles crucial stress sensors in mediating cellular adaptation to the microenvironment. Unsurprisingly, such plasticity is often hijacked by tumour cells and multiple elements of mitochondria biology, including mitochondrial metabolism, dynamics and oxidative stress are involved in oncogenesis [18,19,24].

Interestingly, recent evidence revealed that NF-κΒ signalling impinges on mitochondrial functions to drive tumorigenesis and, reciprocally, NF-κΒ is part of the mitochondria-driven signalling network that sustains malignancy. Therefore, we will review how NF-κB pathway and mitochondria cross paths in cancer and the significance of such interplay for anticancer therapy.

2. Mitochondria and Cancer

2.1 Mitochondrial metabolism

Mitochondria are often referred to as the powerhouse of the cell, due to their essential bioenergetic and biosynthetic roles. Fatty acid oxidation (FAO), Krebs cycle (TCA cycle) and OXPHOS take place in these organelles, making them the main sites of energy transformation and ATP production in aerobic conditions [23]. Beyond ATP production, mitochondrial respiration is responsible for the replenishment of electron-carrier cofactors nicotinamide adenine dinucleotide (NAD+) and flavin adenine dinucleotide (FAD+) [25,26]. Mitochondria also provide building blocks to feed anabolic pathways via anaplerosis [23]. Whether mitochondria serve biosynthetic or bioenergetic function depends on the environmental conditions.

Due to their ability to adapt, mitochondria represent an indispensable resource for cancer cells, which need metabolic plasticity to survive unfavourable TME [24]. Hence, metabolic reprogramming has been recognised as a core hallmark of cancer [3,27,28]. Although Warburg’s assumptions have relegated the mitochondrial respiration into second place for decades, it is now well recognised that many types of cancer generate most of their cellular energy via oxidative phosphorylation [20,29]. Cancer cells undergo sequential metabolic reprogramming during the process of tumorigenesis [20,30,31]. While during tumour progression bioenergetic defects seems to be advantageous [30,32–35], several works in different cancer models, including breast, melanoma and colon cancer, suggested that mitochondrial metabolism plays a major role in metastatic spread and drug resistance [36–45]. Mitochondrial metabolism seems also to be a key aspect of the cross-talk between stromal and cancer cells. Energy-rich fuels, such as lactate and pyruvate, are exploited by cancer cells to fuel OXPHOS and sustain their anabolic needs [46]. Transfer of lipids from adipocytes to ovarian cancer cells provided energy for rapid tumour growth and promoted ovarian cancer metastasis [47]. Moreover, mitochondrial DNA transfer from stromal to cancer cells restored OXPHOS in tumour cells defective in mitochondrial respiration, thus increasing their ability to metastasize [48].

2.2 Mitochondrial dynamics

Mitochondria are not isolated organelles but are a dynamic network continually undergoing fusion to form larger mitochondria and fission to break up into smaller bodies. The balance between these two processes determines mitochondria morphology. Mitochondrial fusion involves outer membrane fusion followed by inner membrane fusion. The fusion machinery relies on the GTPases mitofusin 1 (Mfn1) and mitofusin 2 (Mnf2) for the outer membrane fusion while inner membrane fusion is mediated by optic atrophy 1 (OPA1). The inverse process of mitochondrial fragmentation is driven by the cytosolic GTPase dynamin 1-like protein (DMN1L/Drp1), which is recruited to the mitochondrial surface where it interacts with several DRP1 receptors, including mitochondrial fission factor (MFF). Mitochondrial shape is tightly connected with the functionalities of these organelles and in particular with mitochondrial metabolism. While mitochondrial fusion protects from mitophagy, preserves mitochondrial activity and sustains ATP production, mitochondrial fission isolates dysfunctional mitochondria, avoiding excessive reactive oxygen species (ROS) generation [49–51]. Therefore, mitochondrial fusion is increased in condition of nutrients depletion and has been associated with increased OXPHOS [52–54], while the fragmentation of mitochondria is induced by hypoxia and is often concomitant with reduced mitochondrial respiration [55,56]. Mitochondrial dynamics also affect cell cycle progression and susceptibility to apoptosis [57,58].

There is extensive evidence relating the imbalance of fission and fusion to cancer progression in several types of tumours [57,59]. In particular, the majority of studies described a fragmented mitochondrial network in cancer cells, supporting a pro-tumorigenic role for fission [57,59]. The impairment of mitochondrial fragmentation through Dnrp1 knockdown/inhibition or Mfns overexpression reduced cancer cell growth and increased apoptosis both in vitro and in vivo in several cancer models [59,60], while increased Drp1 expression has been associated with aggressiveness and stem-like phenotype [19,57,59,61–63]. In agreement with these findings, altered mitochondrial dynamics, increased ROS production and OXPHOS impairment have been described in K-Ras-transformed cells, with oncogenic K-Ras promoting mitochondrial fission via Drp1 activation [64,65]. Although the opposing force of mitochondrial fusion seems to counteract tumour progression in most of the cases [51], c-myc has been reported to affect mitochondrial dynamics and promote malignant growth by increasing mitochondrial fusion [66]. Hence, further investigations are needed to clarify how oncogenic pathways impact mitochondrial dynamic to promote tumour development e progression.

2.3 Oxidative stress

Mitochondria are a major contributor of cellular ROS [67,68]. Successful tumours maintain ROS levels within a specific window which promotes cancer growth without causing toxicity [19]. In fact, while low levels and high levels of ROS are associated with cellular homeostasis and apoptosis, respectively, a sub-lethal intermediate ROS production has been associated with cancer progression; accordingly, cancer cells often display enhanced ROS generation compared to normal cells [29,69]. ROS production is exacerbated in cancer as result of oncogenic signals, mutation of the electron transport chain (ETC) machinery as well as hypoxic microenvironment, and affects tumorigenesis by activating oncogenic signalling pathways, altering metabolism and affecting the expression and post-translational modifications of proteins involved in regulating mitochondrial dynamics [69–71]. ROS production also correlated with metastatic potential in multiple tumour types and the metastatic spread was blocked by ROS scavengers [36]. If ROS levels increase above the sub-lethal threshold, many tumours upregulate protective antioxidant pathways as demonstrated by the fact that antioxidant treatments can promote metastasis and invasiveness [72,73].

3. NF-κΒ and Mitochondria in cancer

3.1NF-κΒ bioenergetic functions

Metabolic adaptation in hostile environments and efficient immune responses against infections are basic requirements which must be meet by all living organisms to survive. These physiological challenges are both of paramount importance and energy intensive and need to be coordinated so that cellular homeostasis could be preserved [74,75]. This need clearly manifest itself in the tight coevolution and integration of inflammatory and metabolic pathways and NF-κΒ is a good example of this interconnection [75,76]. This transcription factor is best known for its central role in immunity, inflammation and cancer, where it coordinates many signals driving cell activation, survival and proliferation [1–4]. All these processes require energy, hence, the fascinating idea that NF-κΒ could reprogram cellular metabolic networks to sustain proliferation.

Kawauchi et al. reported that IKK/NF-κΒ pathway activation caused increased glucose uptake and glycolytic flux in p53-/- mouse embryonic fibroblasts (MEFs) via the upregulation of the gene encoding for the glucose transporter Glucose transporter 3 (GLUT3). This increased intracellular levels of glucose and enhanced glycolysis were associated with the O-linked-b-N-acetyl-glucosammine (O-GlcNAc) modifications of IKK on several serine residues, leading to IKK/NF-κΒ activation. Interestingly, this positive feedback loop involving glycolysis and NF-κΒ pathway was demonstrated to promote H-Ras-mediated transformation, piecing together for the first time NF-κΒ oncogenic function and cellular metabolism [8].

As it could be expected, NF-κΒ involvement is not just about glycolysis, but several works pointed out a role for NF-κΒ in regulating mitochondrial respiration and, interestingly, this NF-κΒ bioenergetic function has been demonstrated to be critically dependent on the p53 status of the cell. Indeed, Johnson et al. demonstrated that in both MEF and cancer cells lacking p53, the NF-κΒ member RelA translocated into the mitochondria, where it repressed mitochondrial gene expression, including cytochrome c and cytochrome b oxidase III, thus dampening oxygen consumption and ATP levels. Interestingly, the transcriptional regulation of mitochondrial genome by NF-κΒ was retained following mutation of a critical residue in the DNA binding domain, while it requires the C-terminal transactivation domain, suggesting that NF-κΒ affects the transcription program by directly interacting with mitochondrial transcription factors [9]. The authors proposed that this direct control of mitochondrial genome by NF-κΒ and the consequent suppression of mitochondrial respiration in favour of glycolysis could contribute to the Warburg effect so often observed in cancer cell. At the same time, it could be a complementary mechanism supporting the model of Kawauchi et al. in which, in absence of p53, NF-κΒ induced both glycolytic gene expression and flux.

The significance of this p53 independent-NF-κΒ role in regulating oxidative respiration in cancer have some limitations, due the fact that inactivation of both p53 alleles by mutations is an extremely rare event in tumour cells. Therefore, the understanding of how this bioenergetic function of NF-κΒ is affected by the presence of wild type or mutated p53 is certainly relevant. The study of Johnson et al. demonstrated across a panel of cancer cell lines that wild type p53 prevents the mitochondrial shuttle of RelA by inhibiting its interaction with the heat shock protein Mortalin/mitochondrial HSP70, responsible of RelA translocation to mitochondria. When RelA is kept outside the mitochondria, its impact on cellular metabolism is diametrically opposite, leading to the upregulation of OXPHOS, most likely via the transcriptional regulation of nuclear metabolic genes. Accordingly, the silencing of RelA in p53-expressing cells resulted in decreased oxygen consumption and ATP production, while in p53-deficient cells the same silencing caused an increase of both OXPHOS and ATP levels [9].

In agreement with these findings, Mauro et al. identified NF-κB as a central regulator of mitochondrial respiration and established a role for NF-κB/p53 axis in metabolic adaptation in normal cells and cancer. The inhibition of NF-κΒ/RelA in early passage MEF wild type for p53 resulted in decreased oxygen consumption and glycolytic reprogramming, with augmented glucose consumption and lactate production. When cultured under glucose limitation, RelA-deficient MEF failed to meet the energy demand, resulting in necrotic cell death. The metabolic crisis faced by MEF following RelA inhibition was best exemplified by OXPHOS impairment and dropped ATP levels. These findings suggested that NF-κΒ pathway is part of the nutrient/energy sensing cell machinery and govern energy homeostasis and metabolic adaptation by controlling the balance between glycolysis and respiration for energy provision. This NF-κΒ-dependent metabolic pathway involved p53. The authors showed that p53 was under direct transcriptional control by NF-κΒ and that RelA deficiency caused a marked reduction of p53 expression, both in basal and under glucose starvation conditions [7]. In contrast, NF-κΒ did not affect p53 protein stability, which is controlled by AMP-activated protein kinase (AMPK), the principal low-energy sensor in most eukaryotic cells [77], thus supporting a model in which both NF-κΒ and AMPK are required to engage p53 pathway to direct the cellular response to metabolic stress. This NF-κΒ/p53 bioenergetic axis controlled the cellular metabolic adaptation by upregulating SCO2 (mitochondrial synthesis of cytochrome c oxidase 2), a critical assembly factor of the cytochrome c oxidase (COX)(Complex IV) of the mitochondrial ETC [7,78,79]. Accordingly, SCO2 reconstitution restored respiration and survival in RelA-deficient cells, suggesting that SCO2 is a key downstream effector of the NF-κΒ/p53 bioenergetic function.

Interestingly, the significance of this NF-κΒ-dependent upregulation of mitochondrial respiration extends beyond physiology and takes up the dichotomy between pro- and anti-oncogenic function of NF-κΒ. Indeed, RelA was demonstrated to suppress H-Ras(V12) oncogenic transformation in vitro by inducing p53/SCO2 pathway, and in so doing, limiting the Warburg effect [7]. However, the same NF-κΒ-mediated bioenergetic pathway has been shown to promote tumorigenesis. In CT-26 colon carcinoma cells, a model system in which NF-κB plays a pro-tumorigenic role, RelA deficiency impaired metabolic adaptation during metformin-induced metabolic crisis both in vitro and in vivo [7]. These findings indicate that NF-κΒ enables cancer growth during metabolic stress, a condition experienced by most cancers, which have to survive under low nutrient and oxygen supply.

It remains to determine how this regulation of mitochondrial respiration by NF-κΒ is affected by mutant p53, whose role in regulating energy metabolism has not been completely elucidated. Recent evidences showed that mutant forms of p53 can bind to and enhance the stability/activity of NF-κΒ in cancer cells [80–83]. Yet, the metabolic twist of this interplay between NF-κΒ and mutant p53 is not completely clear. Indeed, mutant p53 has been associated to both increased mitochondrial respiration and glycolysis and there are few evidences about the role of NF-κΒ in p53-mutated systems [84–89]. A recent work showed that mutant p53R248Q downregulated mitochondrial biogenesis and OXPHOS and upregulated glycolysis under normoxia and hypoxia in human cervix cancer cells. This glycolytic reprogramming was associated to the increased expression of several transcription factors, including NF-κΒ, c-Myc and HIF-1 [90]. Although the study does not define the precise role of NF-κΒ in this p53R248Q-mediated reprogramming toward respiration, the data support a model in which NF-κΒ promotes Warburg effect in cancer cells, either in lack of p53 or in the presence of the mutant protein. However, Birkenmeier et al. showed that NF-κΒ promoted a metabolic shift toward OXPHOS in classical Hodgkin Lymphoma (cHL) cells featuring either wild type or mutant p53. Indeed, mitochondrial genes, including genes for ATP synthase subunits and involved in ETC, were upregulated in cHL cells compared to normal B cells at multiple differentiation stages. Mitochondrial mass, markers of mitochondrial biogenesis and OXPHOS rates were markedly increased in both cHL cell lines and primary samples. Interestingly, pharmacological inhibition of NF-κΒ pathway by SN50 and IKK-NBD in cHL cell lines caused a reduction in mitochondrial genes expression, oxygen consumption rate and mitochondrial biogenesis, while lactate production was significantly increased [10]. These findings suggest that NF-κΒ increases the OXPHOS capacity of cHL cells via a cell-autonomous mechanism, in presence of either wild type or mutant p53, and this bioenergetic pathway is active regardless of glucose availability.

The ability of NF-κΒ to promote either mitochondrial respiration or Warburg effect may sound controversial, but in fact it mirrors the metabolic plasticity of tumours, that allow cancer cells to boost glycolysis when they are rapidly proliferating, while they switch to OXPHOS when they migrate from the primary site, experience epithelial-mesenchymal transition (EMT), stemness and become resistant to therapies [91]. Although further investigations are needed to best characterize the bioenergetics function of NF-κΒ in cancer, its involvement in the control of metabolic processes and reprogramming have profound implication to oncogenesis and anti-cancer therapy.

3.2NF-κΒ role in the reverse Warburg effect

The dynamic crosstalk between TME and tumour cells promotes EMT and tumour aggressiveness [92–100]. This communication most probably evolved to promote homeostasis in normal tissues but can also be hijacked by tumours to promote their growth. The key role of the TME in shaping the metabolism of cancer cells is recognised as a hallmark of cancer [3]. Cancer-associated fibroblasts (CAF) were the first stromal cells reported to be metabolically coupled with cancer cell, leading to the “reverse Warburg effect” theory, a two compartment model, which reconsiders tumour metabolism taking into account the prominent role of TME [46,101–106]. Based on this model, cancer cells reprogram stromal adjacent fibroblasts to undergo aerobic glycolysis and to secrete energy-rich fuels, such as lactate and pyruvate, which, in turn, are exploited by cancer cells to fuel OXPHOS and sustain their anabolic needs. This tumour-stroma metabolic coupling requires two key events to happen, i) the autophagic/lysosomal degradation of stromal Caveolin-1 (Cav-1), a potent inhibitor of nitric oxide synthase, and ii) the upregulation of mono-carboxylate transporters (MCTs).

Cav-1 loss in mesenchymal cells induced oxidative stress, mitochondrial dysfunction and aerobic glycolysis [107]. Oxidative stress triggered by cancer cells and hypoxia were shown to induce the autophagic degradation of Cav-1 [105,106]. Martinez-Outschoorn et al. demonstrated that this process is mediated by HIF-1 and NF-κB upregulation. The cooperation between HIF-1 and NF-κB in promoting the reverse Warburg effect is not surprising, as several evidence has demonstrated their interplay and involvement in regulating metabolic circuitries [7,108–110]. Martinez-Outschoorn and colleagues showed that cancer cells promoted NF-κΒ and HIF-1 activation in adjacent fibroblasts in a paracrine manner, and that the pharmacological inactivation of both HIF-1 and NF-κΒ prevented Cav-1 degradation. Reciprocally, acute loss of Cav-1 was sufficient to trigger NF-κB activation and HIF-1 accumulation, clearly suggesting that in stromal cells, Cav-1 loss and the activation of these two transcription factors are involved in a positive feedback loop, with the NF-κB and HIF-1 upregulation triggering Cav-1 loss and Cav-1 down-regulation further enhancing their activation [105,106]. This feed-forward network triggers the glycolytic catabolism in the tumour stroma, which, in turn, promotes the anabolic growth of adjacent cancer cells, by providing a steady stream of recycled nutrients.

The “forced” transfer of metabolites from CAFs to cancer cells requires the upregulation of Monocarboxylate transporter 4 (MCT4) and Monocarboxylate transporter 1 (MCT1), the so called “lactate shuttle”, respectively involved in the release and uptake of these energy-rich catabolites. In particular, MCT4 is highly expressed in CAF and macrophages and its expression is regulated by HIF-1 and NF-κΒ [102,111–113].

Lactate released in the TME does not serve solely as a nutrient to feed into cancer cell OXPHOS, but it has been rediscovered as signalling oncometabolite acting on both stromal and tumour cells and governing cancer metabolic adaptation, immune response and resistance to therapy, with the ultimate goal to maximise tumour growth [114].

Hence, NF-κB and HIF-1 have been demonstrated to act as lactate-responsive transcription factors in endothelial cells, thus linking cancer metabolism and angiogenesis. Findings from Fearon research group demonstrated that lactate released in the TME was taken up by endothelial cells via MCT1 transporter and activated both HIF-1 and NF-κΒ independently of hypoxia. The activation of NF-κΒ and HIF-1, in turn, supported autocrine IL-8 signalling and VEGF receptor 2 (VEGFR2) expression, respectively, thus promoting angiogenesis and metabolic adaptation to low-nutrient TME [115,116].

Interestingly, lactate is also able to activate HIF-1 in oxidative tumour cells, where it controls metabolism and tumour growth, but not NF-κΒ [117,118]. This could be explained by the fact that while reduction of prolyl hydroxylase domain containing-protein (PHD) enzymes is sufficient for the stabilization of HIF-1 in response to lactate [119], both inhibition of PHDs and NADH-mediated ROS generation by NAD(P)H oxidases (Noxs) are simultaneously and mandatorily required for lactate to activate NF-κB, and oxidative cancer cells use NADH to aliments OXPHOS in mitochondria rather than Noxs in the cytosol [115].

Recently it has been demonstrated that lactate can also strongly affect immune cells function via HIF-1 upregulation [120]. High levels of extracellular lactic acid have been reported to induce the expression of VEGF and arginase-1 (Arg-1) and the macrophage polarization toward the M2 phenotype, which supported tumour progression, metastatic dissemination, and cancer immune evasion [121]. Interestingly, recent evidence by Verzella et al. has demonstrated a role for NF-κΒ in inducing the M2-like polarization of tumour-associated macrophage via GADD45/p38 axis, in order to promote immunosuppression and T-cell exclusion from the TME [122,123]. Considering that NF-κΒ is activated in response to lactate, its role in regulating mitochondrial respiration, and the fact that M2 polarised macrophages are characterized by OXPHOS-dependent metabolism [124–126], it is tempting to speculate that NF-κΒ could affect macrophage polarization also by eliciting the transcriptional program underpinning their metabolic rewiring toward OXPHOS. However, this hypothesis awaits scientific demonstration. There is a bulk of evidence pointing to NF-κΒ and HIF-1 as the master transcription factors responsible for this tumour-TME metabolic coupling.

This metabolic symbiosis between the tumour and the surrounding microenvironment also affects cancer drug response and sustains resistance to anticancer therapies. Recently, Apicella et al. showed that increased lactate secretion by Epidermal Growth Factor Receptor (EGFR)- or Mesenchymal-epithelial transition (MET)-addicted cancer cells following prolonged treatment with tyrosine kinase inhibitors (TKIs) instructed CAFs to produce hepatocyte growth factor (HGF) in a NF-κB-dependent manner. Increased HGF, in turn, activated MET-dependent signalling in cancer cells, thus sustaining resistance to TKIs [127].

Although much remains to be learned about this tumour-TME metabolic coupling, there is a bulk of evidence pointing to NF-κΒ as one of the master transcription factors, along with HIF-1, responsible for this cross-talk.

3.3 NF-κΒ, ROS and mitochondrial dynamics

The reciprocal connection between mitochondrial structure and ROS production is well established [128,129]. As NF-κΒ acts as oxidative stress response transcription factors, it is not surprising neither that NF-κΒ pathway can affect mitochondria dynamics [130] and, reciprocally, mitochondrial structure can impact on NF-κΒ activation, nor that this reciprocal regulation plays a part in cancer.

MEF lacking IKK, but not MEF lacking IKK, showed a fragmented mitochondrial network and a reduced expression of OPA1 protein, one of the major regulators of mitochondrial fusion. Ectopic expression of IKK rescued this mitochondrial phenotype, suggesting that the non-canonical NF-κΒ pathway plays an important role in regulating mitochondrial dynamics [131]. Accordingly, NF-κΒ inducing kinase (NIK), another principal component of the non-canonical NF-κΒ pathway, has been demonstrated to induce mitochondrial fission in MEF cancer cells and ex vivo tumour tissue by recruiting Drp1. Consistently, NIK or Drp1 silencing was associated with decreased ROS levels and mitochondrial fragmentation [132]. Recent evidence pointed out for the involvement of the NF-κΒ canonical pathway in controlling mitochondrial dynamics, by demonstrating that insulin was able to increase OPA-1 expression and mitochondrial fusion via Akt-mTor-NF-κΒ (Protein kinase B-mammalian Target of rapamycin- NF-κΒ) pathway in cardiomyocytes [133].

Whilst it is true that NF-κΒ can impact mitochondria dynamics, it also true that, reciprocally, mitochondria can sense stress signals and convert them into a cell biological response leading to NF-κΒ activation. Zemirli et al. demonstrated that under physiological condition, stressed-induced mitochondrial hyperfusion promoted NF-κΒ activation through the mitochondrial E3 ubiquitin ligase MULAN, thus sustaining cell survival [134].

Given the importance of mitochondrial dynamics in maintaining ROS levels [135], it is not surprising that mitochondrial morphology impinges on cancer dynamics at least in part via ROS-mediated signalling. Hence, aberrant mitochondrial dynamics may trigger a vicious cycle by increasing ROS production, which, in turn, may affect mitochondrial structure and exacerbate oxidative stress, thus sustaining survival and tumour growth. Increased mitochondrial fission mediated by forced expression of Drp1 or MNF1 knockdown promoted HCC survival both in vitro and in vivo through the ROS-mediated regulation of NF-κΒ and p53 pathways [136,137]. Mechanistically, mitochondrial fragmentation-dependent ROS production activated Akt, which, in turn, coordinately increased NF-κΒ activation by activating IKK and inhibiting IBα and promoted p53 degradation by activating Mdm2. Accordingly, treatment of HCC cells with the ROS scavenger N-acetylcysteine (NAC), restored p53 expression while dampening NF-κΒ activation. Reduced NF-κΒ signalling and ROS production were also observed after Drp1 knockdown or MNF1 overexpression, thus confirming the importance of mitochondrial fission/ROS/NF-κΒ as a critical survival axis in HCC [136]. Zhan et al. further demonstrate that the activation of NF-κB pathway induced by Drp1-mediated mitochondrial fission also promoted cell proliferation through the upregulation of cyclin D1 and cyclin E1 [137]. Recently, Deet et al. showed that macrophage migration inhibitory factor (MIF)-dependent NF-κΒ activation was essential for maintaining mitochondrial dynamic balance and cancer cell survival. Mitochondrial pathology and cell death associated with MIF knockdown was recapitulated by NF-κΒ silencing, while its overexpression was sufficient to rescue mitochondrial structural, functional homeostasis and cell viability [138]. As cancer is not a stand-alone entity, mitochondrial dynamics in tumour-associate cells in the TME are equally important in tumours. Mitochondrial fission factor (MFF) overexpression in immortalised fibroblasts induced mitochondrial fission and dysfunction. MFF-overexpressing fibroblasts were characterised by ROS production, OXPHOS impairment, glycolytic reprogramming along with NF-κΒ activation. The metabolic shift toward glycolysis was associated with increased levels of lactate release, which supported and accelerated the tumour growth in breast cancer-bearing mice in a paracrine manner, thus confirming the energy transfer between stromal and malignant cells [139].

4. Targeting opportunities

4.1 Targeting metabolic processes

Metabolic alterations represent a new promising therapeutic target for cancer treatment. Several agents, tested in preclinical and clinical studies in several tumour models, are able to inhibit bioenergetic and biosynthetic pathways and metabolic processes (i.e. mitochondrial biogenesis, dynamics, oxidative stress). Some of them have been approved by Food and Drug Administration (FDA) and clinical trials as single agents or in combination therapy, are ongoing [22,23,42,46]. In fact, in order to reverse the hyperglycolytic state of cancer cells, inhibitors of glycolysis, such as the glucose competitor 2-deoxy-d-glucose (2DG), the pyruvate analogue dichloroacetate (DCA), GLUTs blockers, MCT-1 and Akt inhibitors, have been investigated in numerous preclinical and clinical studies [23,46,140–148].

Recent evidence demonstrated that some cancers are reliant on OXPHOS [22]. Therefore, alterations in mitochondrial respiration and mitochondrial processes, including mitochondrial biogenesis, dynamics and oxidative stress, represent promising therapeutic targets for cancer treatment [22,23,42,46].

Drugs inhibiting OXPHOS have been widely studied, including the ETC inhibitors Metformin, arsenic trioxide and atovaquone, as well as isocitrate dehydrogenase (IDH) inhibitors [21,22,46,140,149–158]. Mitochondrial division inhibitors-1 (Mdivi-1) was shown to reduce Drp1 activity, but due to its unclear specificity, solubility and potency, the use of this compound in clinic remains an open window [159–161]. Vitamin C and γ-glutamylcysteine synthetase inhibitors, both reducing GSH levels, as well as Nuclear factor-like 2 (NRF2) blockers, which reduce oxidative stress, showed promising results in preclinical and/or clinical models [162–171].

4.2 The therapeutic challenge of targeting NF-κΒ

In the last 30 years, the development of NF-κΒ inhibitors for cancer treatment has been of major pharmaceutical interest. Given the dose limiting toxicities, conventional NF-kB-targeting drug, such as proteasome or IKK inhibitors, were proven unsuccessful in clinic [172,173]. However, the discovery that NF-κΒ was also involved in energy metabolism accelerated the development of specifically anticancer therapeutics targeting the NF-κΒ metabolic functions.

Recent studies pointed out IT-901 as a new small-molecule able to inhibit the NF-κΒ subunit c-Rel, by preventing its binding to DNA both in vitro and in vivo, although with little toxicity [174]. Shono and colleagues demonstrated that IT-901 significantly inhibited tumour growth in a xenograft model of human EBV-induced B-cell lymphoma with no effects on normal B lymphocytes and T cell activity, as well as in models of graft-versus-host disease (GvDH) and graft-versus-lymphoma (GvL). They also showed that IT- 901 inhibited the growth of human Diffuse large B cell lymphoma (DLBCL) cells, in vitro, by reducing proliferation of viable DLBCL cell lines and modulating cytokine profile. The anti-neoplastic activity of IT-901 was due to the selective induction of oxidative stress in B cell lymphoma cells, as demonstrated by the increased ROS production, reduced GSH and antioxidant genes levels and enhanced iNOS activity. No increased levels of ROS were reported in normal leukocytes. Another study conducted by Vaisitti and colleagues showed that IT-901 blocked p65 activity by inducing its degradation in primary NF-κΒ-dependent Chronic lymphocytic leukemia (CLL) [175]. They observed a dose-dependent increased mitochondrial ROS production both in primary and CLL cell lines, resulting in a remarkable decrease of ATP production. Furthermore, a decrease in ROS-mediated mitochondrial membrane potential and the impairment of mitochondrial respiration were seen in vitro, due to the reduced expression of NF-κB-regulated genes, including SCO2, ATP5A1, genes involved in scavenging processes, including catalase, and genes encoding for molecules involved in the cross-talk between tumour and stromal cells. Vaisitti and colleagues demonstrated that IT-901 induced caspase 3 mediated-apoptosis in a dose-dependent manner in primary CLL and RS (Richter syndrome) samples, but not in healthy B and T cells. The drug also inhibited the tumour-promoting phenotype of stromal cells by repressing the expression of integrins and immune-modulatory molecules regulated by NF-κB, including ITGA4, ICAM-1 and VCAM-1, CD86 and CD274. The same results were observed in vivo, where IT-901 significantly reduced tumour growth and metastatic spread of tumour cells in surrounding tissues [175]. These findings indicate that IT-901 acts by inducing oxidative stress, which in turn, impair OXPHOS, leading to apoptosis of cancer cells and disruption of TME-tumour interaction. Promising results were obtained using IT-901 in combination with ibrutinib, a Bruton’s tyrosine kinase (btk) inhibitor. Although mice treated for two weeks did not exhibit any apparent side effects [175], it may be too early to pop the champagne. In fact, in light of the toxicity shown by conventional NF-κB/IKK inhibitors, supplementary investigations of safety, tolerability and therapeutic efficacy in clinical settings of IT-901 should be conducted. Despite the need of further evaluations, these data provide preclinical proof-of concept for IT-901 as a novel selective therapeutic drug to treat human cancers alone or in combination therapy.

5. Concluding Remarks and Future Perspective

Mitochondria actively contribute to tumorigenesis and the plasticity that mitochondria endow to malignant cells allow for their survival in unfavourable environmental conditions, such as starvation, hypoxia and cancer treatments. This renovated attention to mitochondria opened up new therapeutic options, leading to the development of many agents targeting mitochondrial metabolism. However, translating metabolic target into clinical settings, overcoming general toxicities, has proved to be a hard challenge, due to the metabolic similarity between cancer and normal cells, in particular immune effector cells [176,177]. In such scenario, the understanding of the involvement of NF-κΒ and other molecular players in mitochondria-related oncogenic functions is extremely relevant for identifying better targets for therapeutic intervention. To date, despite the aggressive efforts by the pharmaceutical industry to develop a specific NF-κB inhibitor, none has been clinically approved, due to the dose-limiting toxicities associated with the global suppression of NF-κB [172]. Recently, the targeting of an essential downstream effector of the NF-κΒ pro-survival axis in multiple myeloma demonstrated cancer selective therapeutic specificity, thus circumventing the limitations of conventional IKK/NF-κB-targeting drugs [178,179]. Therefore, an increased knowledge of the transcriptional programs sustaining NF-κΒ-mediated bioenergetic functions, as well as how NF-κΒ interfaces with mitochondrial dynamics and oxidative stress is of paramount importance to safely inhibit this pathway and these organelles in cancer.

Acknowledgments

The work was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC) grants 1432 and 5172 and MIUR PRIN grant n° 2009EWAW4M_003 to F.Z., MIUR FIRB grant n° RBAP10A9H9 to E.A, Cancer Research UK programme grant A15115, Medical Research Council (MRC) Biomedical Catalyst grant MR/L005069/1 and Bloodwise project grant 15003 to G.F.

D.V. and B.D.F. were supported by the L’Aquila University Ph.D. program in Experimental Medicine.

Competing Financial Interests

The authors declare no competing financial interests.

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Figure Legends

Fig. 1. NF-κB and mitochondria in cancer. The a