Abstract |
Due to its ability to regulate the growth, differentiation and apoptosis of cancer cells, retinoic acid (RA) is considered a signaling molecule with promising therapeutic potential in oncology. In this study, we show that RA is able to induce the intrinsic ability of breast cancer cells to recognize double-stranded RNA (dsRNA) through the upregulation of Toll-like receptor 3 (TLR3) expression. RA, co-administered with the dsRNA mimicker polyinosinic-polycytidylic acid ( poly(I:C)), synergizes to mount a specific response program able to sense dsRNA through the concurrent upregulation of TLR3, the dsRNA helicases melanoma differentiation-associated antigen-5 (MDA-5) and RA-inducible gene-1 (RIG-1), and the dsRNA-activated protein kinase (PKR) expression, leading breast cancer cells to specifically express downstream transcriptional targets of dsRNA sensors, such as interferon-β (IFNβ), interleukin-8 (IL-8), chemokine (C-C motif) ligand 5 (CCL5), and C-X-C motif Chemokine 10 (CXCL10). A TLR3-dependent apoptotic program is also induced by RA and poly(I:C) co-treatment that correlates with the induction of the tumor necrosis factor ( TNF)-related apoptosis-inducing ligand (TRAIL) and contributes to block breast cancer cell proliferation. The mechanisms of apoptosis induced by RA/ poly(I:C) in breast cancer cells involve type I IFN autocrine signaling, caspase-8 and caspase-3 activation, as well as TRAIL signaling. Our results reveal important links among RA, TLR3 and TRAIL and highlight the combined use of RA and poly(I:C) as a potential effective tumor therapy by improving the apoptotic response of cancer cells with low sensitivity to the action of synthetic dsRNA.
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Authors | A R Bernardo, J M Cosgaya, A Aranda, A M Jiménez-Lara |
Journal | Cell death & disease
(Cell Death Dis)
Vol. 4
Pg. e479
(Jan 31 2013)
ISSN: 2041-4889 [Electronic] England |
PMID | 23370279
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Interferon Type I
- Membrane Proteins
- Nerve Tissue Proteins
- RNA, Double-Stranded
- RNA, Small Interfering
- Receptors, Cell Surface
- Recombinant Proteins
- Robo3 protein, mouse
- TNF-Related Apoptosis-Inducing Ligand
- Toll-Like Receptor 3
- Tretinoin
- Interferon-beta
- eIF-2 Kinase
- Caspase 3
- Caspase 8
- IFIH1 protein, human
- DEAD-box RNA Helicases
- Interferon-Induced Helicase, IFIH1
- Poly I-C
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Topics |
- Apoptosis
(drug effects)
- Breast Neoplasms
(metabolism, pathology)
- Caspase 3
(metabolism)
- Caspase 8
(metabolism)
- Cell Line, Tumor
- Cell Proliferation
(drug effects)
- DEAD-box RNA Helicases
(metabolism)
- Drug Synergism
- Female
- Humans
- Interferon Type I
(metabolism)
- Interferon-Induced Helicase, IFIH1
- Interferon-beta
(genetics, metabolism, pharmacology)
- Membrane Proteins
(metabolism)
- Nerve Tissue Proteins
(metabolism)
- Poly I-C
(pharmacology)
- RNA Interference
- RNA, Double-Stranded
(metabolism)
- RNA, Small Interfering
(metabolism)
- Receptors, Cell Surface
- Recombinant Proteins
(biosynthesis, genetics, pharmacology)
- Signal Transduction
(drug effects)
- TNF-Related Apoptosis-Inducing Ligand
(antagonists & inhibitors, genetics, metabolism)
- Toll-Like Receptor 3
(antagonists & inhibitors, genetics, metabolism)
- Transcriptional Activation
- Tretinoin
(pharmacology)
- Up-Regulation
(drug effects)
- eIF-2 Kinase
(metabolism)
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