Synergy between RA and TLR3 promotes type I IFN-dependent apoptosis through upregulation of TRAIL pathway in breast cancer cells.
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.
Department of Endocrine and Nervous System Physiopathology, Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Madrid, Spain.
A R
AR
Bernardo
J M
JM
Cosgaya
A
A
Aranda
A M
AM
Jiménez-Lara
D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism*; D000072640:Interferon-Induced Helicase, IFIH1; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology; D034622:RNA Interference; D012330:RNA, Double-Stranded / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051196:Toll-Like Receptor 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014212:Tretinoin / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects*; D019892:eIF-2 Kinase / Q000378:metabolism; D000097905:Roundabout Proteins
D053148:Caspase 3; D053181:Caspase 8; D053487:DEAD-box RNA Helicases; D007370:Interferon Type I; D000072640:Interferon-Induced Helicase, IFIH1; D016899:Interferon-beta; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011070:Poly I-C; D012330:RNA, Double-Stranded; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; D051196:Toll-Like Receptor 3; D014212:Tretinoin; D019892:eIF-2 Kinase; C118348:Robo3 protein, mouse; D000097905:Roundabout Proteins; C452815:IFIH1 protein, human