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 [email protected]
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: [email protected]
Daniela Verzella: [email protected]
Barbara Di Francesco:
[email protected]
Edoardo Alesse: [email protected]
Guido Franzoso: g.franzoso@ imperial.ac.uk
Francesca Zazzeroni: [email protected]
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