| Laboratory of Ana María Jiménez Lara |
Crosstalk between retinoids and innate immune signaling in cancer
The search for therapies to manage breast cancer constitutes an area of intensive research. 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. Transcriptome analysis using microarrays from breast cancer cell lines treated with RA has revealed a striking regulation of different transcription programs. Among them, Toll-like Receptor 3 (TLR3) arises as a interesting target for RA. We found that RA is able to induce the intrinsic ability of breast cancer cells to recognize double-stranded RNA (dsRNA) through the upregulation of 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 Retinoic acid-Inducible Gene-1 (RIG-1), and the dsRNA-activated Protein Kinase (PKR) expression, driving ultimately breast cancer cells to die by a TRAIL (Tumor-Necrosis-Factor Related Apoptosis-Inducing Ligand)- dependent apoptotic program (Cell Death Dis. 2013 Jan 31;4:e479. doi: 10.1038/cddis.2013.5. PMID: 23370279).
In addition, we also found that RA/poly(I:C) co-treatment, synergically, induce the activation of Interferon Regulatory Factor-3 (IRF3) in breast cancer cells. IRF3 activation is mediated by TLR3, since its depletion abrogates IRF3 activation by RA/poly(I:C) co-treatment. Besides induction of TRAIL, apoptosis induced by RA/poly(I:C) correlates with the increased expression of pro-apoptotic TRAIL receptors, TRAIL-R1/2, and the inhibition of the antagonistic receptors TRAIL-R3/4. IRF3 plays an important role in RA/poly(I:C)-induced apoptosis since IRF3 depletion suppresses caspase-8 and caspase-3 activation, TRAIL expression upregulation and apoptosis. Interestingly, RA/poly(I:C) combination synergizes to induce a bioactive autocrine/paracrine loop of type-I Interferons (IFNs) which is ultimately responsible for TRAIL and TRAIL-R1/2 expression upregulation, while inhibition of TRAIL-R3/4 expression is type-I IFN-independent (Apoptosis. 2017 Jul;22(7):920-932. doi: 10.1007/s10495-017-1377-z. PMID: 28409399). Our findings reveal important links among RA, TLR3, IRF3, type-I IFNs 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.