Article

A novel facet of tumor suppression by p53: Induction of tumor immunogenicity

Department of Microbiology
OncoImmunology (Impact Factor: 6.27). 07/2012; 1(4):541-543. DOI: 10.4161/onci.19409
Source: PubMed

ABSTRACT

Pharmacological reactivation of the p53 tumor suppressor is a promising strategy for anti-cancer therapy due to its high potential to elicit apoptosis or growth arrest in cancer cells. Recently we uncovered the mechanism of activation of the innate immune response by p53 upon its activation by small molecules.

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© 2012 Landes Bioscience.
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A novel facet of tumor suppression by p53
Induction of tumor immunogenicity
Hai Li,
1
Tadepally Lakshmikanth,
1
Ennio Carbone
1,2
and Galina Selivanova
1,
*
1
Department of Microbiology; Tumor and Cell Biology; Karolinska Institutet; Stockholm, Sweden;
2
Tumor Immunology Laboratory; Department of Experimental and Clinical Medicine;
University of Catanzaro Magna Graecia; Catanzaro, Italy
Keywords: p53, NKG2D, ULBP2, innate immunity, cancer
Pharmacological reactivation of the p53 tumor suppressor is a promising strategy for anti-cancer therapy due to its high
potential to elicit apoptosis or growth arrest in cancer cells. Recently we uncovered the mechanism of activation of the
innate immune response by p53 upon its activation by small molecules.
Cell-intrinsic barrier mediated by tumor
suppressors and cell-extrinsic barrier medi-
ated by the immune system are the main
defenses of our body against oncogenesis.
Only those cells, which escaped from both
barriers, have the opportunity to develop
into tumor. Innate immunity among the
cell-extrinsic barrier is a front-line defense
against infectious diseases and malignan-
cies, of which NK cells constitute an
important component.
1,2
p53 tumor suppressor is widely recog-
nized as a master regulator of cell-intrinsic
anti-tumor defenses via induction of
growth arrest, apoptosis, senescence,
autophagy, and inhibition of cancer cells
metabolism.
3
Albeit functionally inactive,
p53 is expressed in cancers, leading to
the idea of p53 reinstatement as a novel
therapeutic strategy against human cancers.
Several p53-reactivating compounds are
currently being tested in Phase I clinical
trials, including mutant p53-reactivating
PRIMA-1 analog APR -246, derivative of
MDM2 inhibitor nutlin3a RG7112 and
compounds from Johnson and Johnson.
3
For the successful application of p53-
based therapies in the clinic, a more
rigorous determination of p53 activities
upon its pharmacological reinstatement in
cancer cells is of utmost importance.
Strikingly, apart from well-characterized
cell-intrinsic mechanisms, p53 might also
play a role in modulating the cell-extrinsic
anti-cancer defense. This is suggested by
recent study in mice with switchable
p53 which demonstrated p53-dependent
tumor regression due to the elimination of
senescent cancer cells by innate immune
system.
4
This new facet of p53 tumor
suppression function along with the regu-
lation of cell-intrinsic defenses may greatly
increase the probability to achieve a
durable therapeutic success upon phar-
macological reactivation of p53. However,
the exact molecular mechanism underly-
ing the stimulation of innate anti-cancer
response by p53 is currently unknown.
In our recent study, we applied a
set of p53-reactivating compounds,
PRIMA-1
MET
, Nutlin3a, RITA and a low
dose of Actinomycin D, as a tool to
address whether and how p53 can stimu-
late the immune response against cancer
cells. We found that pharmacological
reactivation of p53 enhanced the NK
cell-mediated killing of samples derived
from patients with metastatic tumors of
different origin, including melanoma,
pancreatic, breast, co lon and lung carci-
noma, as well as established lines, derived
from different carcinomas, osteosarcoma
and lymphoma. We further demonstrated
that this effect is due to the induction of
ULBP2, a ligand of NK cell rec eptor
NKG2D, an importa nt component of the
front-line immune defense against infec-
tious diseases and malignancies. Further-
more, we found that the binding of p53 to
its response element (RE) within the first
intron of ULBP2 gene is required for the
activation of its expre ssion, thus establish-
ing ULBP2 as a bona fide p53 target
gene and suggesting a direct effect of p53
on stimulation of anti-cancer immune
response.
1
Notably, the induction of
ULBP2 by p53 was also recently reported
in an independent study by Textor et al.
2
However, stabilization of p53 by differ-
ent agents is necessary, but not sufficient
for binding of p53 to ULPB2 gene and
ULPB2 induction. In spite of a similar
extent of p53 stabilization, different p53
activating compounds have distinct effect
on ULBP2 expression.
1
Recently proposed model suggests that
p53 activation in vivo includes three major
steps: (1) p53 stabilization, (2) antirepres-
sion (i.e., release from MDM2), and
(3) promoter-specific activation, involving
the binding to different cofactors and
distinct post-translational modifications,
so calle d barcode.
5,6
In addition, the
binding of p53 to its specific RE in DNA
can be determined by the epigenetic
modifications of the promoter.
We found that the p53 RE in ULBP2
gene is highly methylated in cancer cells,
which prevents p53 binding. Demethyla-
tion of the p53 RE in ULBP2, achieved
through repression of DNA methyltrans-
ferases (DNMTs), is required for the
interaction of p53 with its binding site
and the subsequent induction of ULBP2
by p53 (Fig. 1A).
1
*Correspondence to: Galina Selivanova; Email: Galina.Selivanova@ki.se
Submitted: 01/15/12; Accepted: 01/18/12
http://dx.doi.org/10.4161/onci.19409
AUTHOR'S VIEW
OncoImmunology 1:4, 541543; July 2012;
G
2012 Landes Bioscience
www.landesbioscience.com OncoImmunology 541
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© 2012 Landes Bioscience.
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Although our study provides an evi-
dence for the repression of DNMTs by
p53 activation, the mechanism determin-
ing the distinct effect of p53 on DNMTs
expression upon activa tion by different
agents remains to be elucidated. It is
tempting to speculate that the repression
of DNMTs b y p53 requires certain post-
translational modifications and/or inter-
action with specific cellular cofactors
induced by RITA, PRIMA-1
MET
and
Actinomycin D, but not by Nutlin3a or
low concentration of RITA. Recently,
wild-type p53 has been shown to nega-
tively regulate DNMT1 expression by
forming a complex with specificity protein
1 (SP1), which binds to the DNMT1
promoter.
7
However, our data do not
support the involvement of SP1 in
DNMT repression by p53, although we
found that SP1 is important for p53-
mediated repression of genes involved in
glycolysis.
8
It is plausibl e, that p53s post-
translational modifications and cofactors
that associate with p53 form the under-
lying basis of the heterogen eity of p53
response, depending on the type and
dose of stimuli as well as cell type.
6
Since there are more than 50 known
p53 partner proteins, which can modulate
p53-mediated regulation of gene expres-
sion, high throughput approaches are
required to identify the bars of the
code, which confer the differential gene
regulation in response to different p53-
activating molecules.
Induction of ULBP2 by p53 we
uncovered may contribute to the pro-
motion of NKG2D ligand expression
upon genotoxic stress reported previously.
9
Furthermore, cellular response to geno-
toxic stress could modulate inhibitory NK
cell ligands as well.
10
Taken together, these
findings are of particular interest as they
link chemotherapy and immunotherapy
and explain the synergistic effects of these
therapeutic approaches observed in clinic.
Further, our data indicate that the com-
bined administration of p53 activating
agents and DNMT inhibitors could be
very beneficial, since it will not merely
induce autonomous effects in tumor
cells but also prevent their escape from
immunosurveillance (Fig. 1B).
References
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Figure 1. Model illustrating the mechanism underlying transcriptional control of ULBP2 by p53 and
proposed therapeutic implications. (A) p53 activated by PRIMA-1
MET
, Actinomycin D, and RITA,
but not Nutlin3a and low concentration of RITA, can induce demethylation of its response element
(RE) within the first intron of ULBP2 gene via the repression of expression of DNMTs. This allows
the interaction of p53 with its RE and the subsequent induction of ULBP2 transcription by p53,
blue, non-methylated DNA; red, methylated DNA. (B) Proposed therapeutic benefit of combined
administration of p53-activating agents and DNMTs inhibitors.
542 OncoImmunology Volume 1 Issue 4
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© 2012 Landes Bioscience.
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