Emerging roles of Nrf2 signal in non-small cell lung cancer

Classical oncogenic pathways such as PI3K and K-ras have been reported to have an
impact on Nrf2 function, as well as some other well-known transcription factors such
as Bach1, estrogen receptor(ER)-?, NF-kappa B, and HIF-1?.

Nrf2 and PI3K

PI3K signal pathway is a classical oncogenic gene as it enhances tumor cell growth,
viability, and metabolism 65]. PI3K inhibitor NVP-BKM120 reduced expression of Nrf2 in squamous lung cancer cells
24]. However, the mechanism involved has not been elucidated. Activated PI3K signal increased
Nrf2 accumulation in nuclear 21], thereby enhancing multiple biological processes including de novo purine nucleotides
synthesis, glutamine metabolism, and pentose phosphate pathway. Among these processes,
enzymes involved in the pentose phosphate pathway provided substrates for purine synthesis
and glutamine metabolism to promote cell proliferation and cytoprotection.

Nrf2 and K-ras

K-ras gene mutations repeatedly occur at a proportion of 20~30 % in NSCLC 66]. Mutated K-ras proteins cause aberrant activation of downstream signal and confer
to cancer cells’ resistance and survival. Lung adenocarcinoma patients harboring K-ras
mutation tended to be chemoresistant and had dismal prognosis 67], 68]. Tao 25] and DeNicola et al. 69] identified that constitutive expression of K-ras mutation G12D enhanced Nrf2 mRNA
levels. Promoter analysis showed that a TPA response element (TRE) located in exon1
of Nrf2 was activated by K-ras. Remarkably, Satoh et al. modeled the process of lung
carcinogenesis with urethane and found that Nrf2
^?/?
mice were rarely associated with K-ras mutation 17]. They also established Nrf2 prevented tumor initiation but promoted progression in
different phases during carcinogenesis.

Nrf2 and Bach1

Bach1, a nuclear transcription factor, was reported to co-localize with Nrf2 in nucleus
in HepG2 cells and attenuate the binding between Nrf2 and ARE 70]. This negative regulation of Bach1 resulted in the balance of redox within cells.
In earlier research of Sun et al., evidences revealed that the repression was mediated
by Ho-1 and its substrates heme 71]. Reichard et al. found that during arsenite-mediated oxidative stress, Bach1 inactivation
allowed Nrf2 binding to Ho-1 promoter and elevating Ho-1 mRNA 72].

Nrf2 and ER-?

Estrogen receptor (ER) is tightly related to the development and biological behavior
of multiple cancers. Researches suggested that ER-? repressed the activity of Nrf2
and the transcription of phase II metabolic enzymes 73], 74]. Further exploration revealed that this repression resulted from the interaction
between ER-? and Nrf2 and required the coordination of ER ligand 17-estradiol 73].

Nrf2 and Sirt1

Acetylation of amino residuals typically stabilized Nrf2 proteins and prevented it
from degradation 75]. Sirt1 is an enzyme primarily engaged in catalyzing protein deacetylation in nucleus
76]. Kawai et al. noticed that CREB-binding protein (CBP) mediated acetylation of Nrf2
and gave rise to its target gene mRNA, while Sirt1 deacetylated Nrf2 and vice versa
77]. By constructing mutations of pK588Q and pK591Q, they unveiled an indispensible role
of lysine residuals on Nrf2 in the process of Sirt1 regulation.

Nrf2 and NF-kappa B

Inflammatory response activation always occurs with elevation of ROS 78]. As a classical pro-inflammatory factor, NF-kappa B has been implicated in the regulation
of Nrf2. Liu et al. found that NF-kappa B subunit p65 specifically deprived CBP from
Nrf2, leading to inhibition of Nrf2 and its downstream genes 79]. Oppositely, Rushworth et al. recently reported that NF-kappa B subunits p50 and
p65 promoted transcription of Nrf2 by binding to a kappa B site in acute myeloid leukemia,
and conferred to resistance to cytotoxic treatment 80]. These findings suggested distinct patterns of crosstalk between NF-kappa B and Nrf2
in different cell contexts.

Nrf2 and HIF-1?

HIF-1? is a key transcription factor mainly monitoring oxygen homeostasis. Under hypoxic
condition, HIF-1? escapes from degradation mediated by prolyl hydroxylase domain proteins
and augments downstream gene expression 81]. In human endothelial cells, Loboda et al. discovered that induction of HIF-1? attenuated
Nrf2-dependent expression of IL-8 and Ho-1 82]. Thereafter, investigator in the realm of colon cancer has identified Nrf2 as an
important factor in activating HIF-1?. Kim et al. found that stably inhibiting Nrf2
signal in colon cancer cell led to attenuated HIF-1? activation, subsequently causing
a reduction of blood vessel formation and vascular endothelial growth factor expression
83].

Nrf2 and Notch1

Notch family consists of a series of intracellular signal mediators with highly conserved
domain 84], 85]. It was reported that Notch1 and Notch3 expressions were closely associated with
NSCLC patients’ progression and prognosis 86]. Wakabayashi et al. found Notch signal activation upregulated Nrf2 and cytoprotective
genes in mouse liver 87]. They also demonstrated that Notch intracellular domain (NICD) assembled to the Rbpj?
site of Nrf2 promoter, leading to the activation of Nrf2 signal. Inversely, Nrf2 activation
induced by ROS enhanced the Notch pathway, thus promoting airway basal stem cells’
self-renewal 88]. Paul et al. identified a putative ARE within Notch1 promoter 88]. More recently, Zhao et al. discovered that ionizing radiation exposure induced Nrf2
activation and knockdown of Nrf2 attenuated Notch1 expression following ionizing radiation
89]. The evidences above indicated a mutual promotion model for the crosstalk of Nrf2
and Notch1.