TY - JOUR
T1 - Toll-like receptor 3 regulates angiogenesis and apoptosis in prostate cancer cell lines through hypoxia-inducible factor 1α
AU - Paone, Alessio
AU - Galli, Roberta
AU - Gabellini, Chiara
AU - Lukashev, Dmitriy
AU - Starace, Donatella
AU - Gorlach, Agnes
AU - de Cesaris, Paola
AU - Ziparo, Elio
AU - del Bufalo, Donatella
AU - Sitkovsky, Michail V.
AU - Filippini, Antonio
AU - Riccioli, Anna
N1 - Funding Information:
Abbreviations: HIF, hypoxia-inducible factor; HUVEC, human umbilical vein endothelial cell; TLR, Toll-like receptor; VEGF, vascular endothelial growth factor Address all correspondence to: Anna Riccioli, PhD, Department of Histology and Medical Embryology, “Sapienza” University of Rome, 00161 Rome, Italy. E-mail: [email protected] 1This work was supported by grants from MIUR PRIN 2007 to E.Z. and from Agenzia Spaziale Italiana no. I/065/08/0-227/(09) to A.F. This work was partially supported by National Institutes of Health grant R21 AI068816-01A1. The authors declare no conflict of interest. Received 28 December 2009; Revised 2 April 2010; Accepted 5 April 2010 Copyright © 2010 Neoplasia Press, Inc. All rights reserved 1522-8002/10/$25.00 DOI 10.1593/neo.92106
PY - 2010/7
Y1 - 2010/7
N2 - Toll-like receptors (TLRs) recognize microbial/viral-derived components that trigger innate immune response and conflicting data implicate TLR agonists in cancer, either as protumor or antitumor agents. We previously demonstrated that TLR3 activation mediated by its agonist poly(l:C) induces antitumor signaling, leading to apoptosis of prostate cancer cells LNCaP and PC3 with much more efficiency in the former than in the second more aggressive line. The transcription factor hypoxia-inducible factor 1 (HIF-1) regulates several cellular processes, including apoptosis, in response to hypoxia and to other stimuli also in normoxic conditions. Here we describe a novel protumor machinery triggered by TLR3 activation in PC3 cells consisting of increased expression of the specific I.3 isoform of HIF-1α and nuclear accumulation of HIF-1 complex in normoxia, resulting in reduced apoptosis and in secretion of functional vascular endothelial growth factor (VEGF). Moreover, we report that, in the less aggressive LNCaP cells, TLR3 activation fails to induce nuclear accumulation of HIF-1α. However, the transfection of 1.3 isoform of hif-l ain LNCaP cells allows poly(l:C)-induced HIF-1 activation, resulting in apoptosis protection and VEGF secretion. Altogether, our findings demonstrate that differences in the basal level of HIF-1 α expression in different prostate cancer cell lines underlie their differential response to TLR3 activation, suggesting a correlation between different stages of malignancy, hypoxic gene expression, and beneficial responsiveness to TLR agonists.
AB - Toll-like receptors (TLRs) recognize microbial/viral-derived components that trigger innate immune response and conflicting data implicate TLR agonists in cancer, either as protumor or antitumor agents. We previously demonstrated that TLR3 activation mediated by its agonist poly(l:C) induces antitumor signaling, leading to apoptosis of prostate cancer cells LNCaP and PC3 with much more efficiency in the former than in the second more aggressive line. The transcription factor hypoxia-inducible factor 1 (HIF-1) regulates several cellular processes, including apoptosis, in response to hypoxia and to other stimuli also in normoxic conditions. Here we describe a novel protumor machinery triggered by TLR3 activation in PC3 cells consisting of increased expression of the specific I.3 isoform of HIF-1α and nuclear accumulation of HIF-1 complex in normoxia, resulting in reduced apoptosis and in secretion of functional vascular endothelial growth factor (VEGF). Moreover, we report that, in the less aggressive LNCaP cells, TLR3 activation fails to induce nuclear accumulation of HIF-1α. However, the transfection of 1.3 isoform of hif-l ain LNCaP cells allows poly(l:C)-induced HIF-1 activation, resulting in apoptosis protection and VEGF secretion. Altogether, our findings demonstrate that differences in the basal level of HIF-1 α expression in different prostate cancer cell lines underlie their differential response to TLR3 activation, suggesting a correlation between different stages of malignancy, hypoxic gene expression, and beneficial responsiveness to TLR agonists.
UR - http://www.scopus.com/inward/record.url?scp=77954995650&partnerID=8YFLogxK
U2 - 10.1593/neo.92106
DO - 10.1593/neo.92106
M3 - Article
C2 - 20651983
AN - SCOPUS:77954995650
SN - 1522-8002
VL - 12
SP - 539
EP - 549
JO - Neoplasia
JF - Neoplasia
IS - 7
ER -