Τίτλος:
Nuclear receptor NR5A2 negatively regulates cell proliferation and tumor
growth in nervous system malignancies
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Nervous system malignancies are characterized by rapid progression and
poor survival rates. These clinical observations underscore the need for
novel therapeutic insights and pharmacological targets. To this end,
here, we identify the orphan nuclear receptor NR5A2/LRH1 as a negative
regulator of cancer cell proliferation and promising pharmacological
target for nervous system-related tumors. In particular, clinical data
from publicly available databases suggest that high expression levels of
NR5A2 are associated with favorable prognosis in patients with
glioblastoma and neuroblastoma tumors. Consistently, we experimentally
show that NR5A2 is sufficient to strongly suppress proliferation of both
human and mouse glioblastoma and neuroblastoma cells without inducing
apoptosis. Moreover, short hairpin RNA-mediated knockdown of the basal
expression levels of NR5A2 in glioblastoma cells promotes their cell
cycle progression. The antiproliferative effect of NR5A2 is mediated by
the transcriptional induction of negative regulators of the cell cycle,
CDKN1A (encoding for p21cip1), CDKN1B (encoding for p27kip1) and Prox1.
Interestingly, two well-established agonists of NR5A2, dilauroyl
phosphatidylcholine (DLPC) and diundecanoyl phosphatidylcholine, are
able to mimic the antiproliferative action of NR5A2 in human
glioblastoma cells via the induction of the same critical genes. Most
importantly, treatment with DLPC inhibits glioblastoma tumor growth in
vivo in heterotopic and orthotopic xenograft mouse models. These data
indicate a tumor suppressor role of NR5A2 in the nervous system and
render this nuclear receptor a potential pharmacological target for the
treatment of nervous tissue-related tumors.
Συγγραφείς:
Gkikas, Dimitrios
Stellas, Dimitris
Polissidis, Alexia and
Manolakou, Theodora
Kokotou, Maroula G.
Kokotos, George and
Politis, Panagiotis K.
Περιοδικό:
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF
AMERICA
Εκδότης:
NATL ACAD SCIENCES
Λέξεις-κλειδιά:
glioblastoma; neuroblastoma; proliferation; LRH1; agonists
DOI:
10.1073/pnas.2015243118|1of12
