Dual Role of TLR3 in Inflammation and Cancer Cell Apoptosis

Estornes, Yann; Micheau, Olivier; Renno, Toufic; Lebecque, Serge

doi:10.5772/54772

Cited by 10 publications

(8 citation statements)

References 128 publications

(154 reference statements)

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“…Activation of the interferon response could be due to various causes, including the accumulation of dsRNAs (Field et al, 1967;Lampson et al, 1967) (Fig 5A). Thus, we next examined the levels of dsRNA sensors (Estornes et al, 2013;Schneider et al, 2014) in our cell lines. Expression of Toll-like receptor 3 (TLR3), a membrane receptor involved in the recognition of long (> 50 nucleotides) dsRNA intermediates of viral replication (Estornes et al, 2013), was largely unchanged in the mutant lines ( Fig 5A and B).…”

Section: Ago1x-deficient Cells Accumulate Dsrnasmentioning

confidence: 99%

“…Thus, we next examined the levels of dsRNA sensors (Estornes et al, 2013;Schneider et al, 2014) in our cell lines. Expression of Toll-like receptor 3 (TLR3), a membrane receptor involved in the recognition of long (> 50 nucleotides) dsRNA intermediates of viral replication (Estornes et al, 2013), was largely unchanged in the mutant lines ( Fig 5A and B). In contrast, the expression of RNA helicase RIG-I (also known as DDX58) and MDA-5 (melanoma differentiation-associated gene 5, also known as interferon induced with helicase C domain 1 or IFIH1) (Estornes et al, 2013), which recognize short and long cytoplasmic dsRNAs, respectively, was significantly increased at the RNA level ( Fig 5B).…”

Section: Ago1x-deficient Cells Accumulate Dsrnasmentioning

confidence: 99%

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Prevention of dsRNA‐induced interferon signaling by AGO1x is linked to breast cancer cell proliferation

et al. 2020

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Translational readthrough, i.e., elongation of polypeptide chains beyond the stop codon, was initially reported for viral RNA, but later found also on eukaryotic transcripts, resulting in proteome diversification and protein‐level modulation. Here, we report that AGO1x, an evolutionarily conserved translational readthrough isoform of Argonaute 1, is generated in highly proliferative breast cancer cells, where it curbs accumulation of double‐stranded RNAs (dsRNAs) and consequent induction of interferon responses and apoptosis. In contrast to other mammalian Argonaute protein family members with primarily cytoplasmic functions, AGO1x exhibits nuclear localization in the vicinity of nucleoli. We identify AGO1x interaction with the polyribonucleotide nucleotidyltransferase 1 (PNPT1) and show that the depletion of this protein further augments dsRNA accumulation. Our study thus uncovers a novel function of an Argonaute protein in buffering the endogenous dsRNA‐induced interferon responses, different than the canonical function of AGO proteins in the miRNA effector pathway. As AGO1x expression is tightly linked to breast cancer cell proliferation, our study thus suggests a new direction for limiting tumor growth.

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Section: Ago1x-deficient Cells Accumulate Dsrnasmentioning

confidence: 99%

Section: Ago1x-deficient Cells Accumulate Dsrnasmentioning

confidence: 99%

Prevention of dsRNA‐induced interferon signaling by AGO1x is linked to breast cancer cell proliferation

et al. 2020

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“…Many types of cancer express TLR3, including breast carcinoma, oral cell squamous and esophageal carcinoma, cervical carcinoma, ovarian carcinoma, prostate carcinoma, head and neck carcinoma, lung squamous cell carcinoma and adenocarcinoma, hepatocellular carcinoma, and melanoma. 8 Like normal cells, cancer cell lines respond to TLR3 ligands by secreting inflammatory cytokines, type I interferon (IFN I), and chemokines, which enhance the recruitment and activation of immune cells.…”

Section: Introductionmentioning

confidence: 99%

“…TLR agonists slow tumor cell proliferation in breast and prostate cancer cell lines, and many studies have reported the apoptotic effects of TLR3 agonists in several tumor histotypes, including breast, melanoma, head and neck, prostate, renal carcinoma, colon, cervical, and lung cancer cells. 8 …”

Section: Introductionmentioning

confidence: 99%

Exploiting poly(I:C) to induce cancer cell apoptosis

Bianchi

Pretto

Tagliabue

et al. 2017

Cancer Biology & Therapy

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TLR3 belong to the Toll-like receptors family, it is mainly expressed on immune cells where it senses pathogen-associated molecular patterns and initiates innate immune response. TLR3 agonist poly(I:C) was developed to mimic pathogens infection and boost immune system activation to promote anti-cancer therapy. Accordingly, TLR agonists were included in the National Cancer Institute list of immunotherapeutic agents with the highest potential to cure cancer. Besides well known effects on immune cells, poly(I:C) was also shown, in experimental models, to directly induce apoptosis in cancer cells expressing TLR3.This review presents the current knowledge on the mechanism of poly(I:C)-induced apoptosis in cancer cells. Experimental evidences on positive or negative regulators of TLR3-mediated apoptosis induced by poly(I:C) are reported and strategies are proposed to successfully promote this event in cancer cells.Cancer cells apoptosis is an additional arm offered by poly(I:C), besides activation of immune system, for the treatment of various type of cancer. A further dissection of TLR3 signaling would contribute to greater resolution of the critical steps that impede full exploitation of the poly(I:C)-induced apoptosis. Experimental evidences about negative regulator of poly(I:C)-induced apoptotic program should be considered in combinations with TLR3 agonists in clinical trials.

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“…TLR3, like other TLRs, is also expressed on epithelial cells, including cancer cells of several histotypes [9]. Similar to immune cells, cancer cells respond to TLR3 ligands by secreting inflammatory cytokines, type I interferon (IFN I), and chemokines, which enhance the recruitment and activation of immune cells.…”

Section: Introductionmentioning

confidence: 99%

TLR3 Expression Induces Apoptosis in Human Non-Small-Cell Lung Cancer

Bianchi

Alexiadis

Camisaschi

et al. 2020

IJMS

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The prognostic value of Toll-like receptor 3 (TLR3) is debated in cancer, differing between tumor types, methods, and cell types. We recently showed for the first time that TLR3 expression on early stage non-small-cell lung cancer (NSCLC) results associated with a good prognosis. Here, we provide experimental evidences explaining the molecular reason behind TLR3’s favorable prognostic role. We demonstrated that TLR3 activation in vitro induces apoptosis in lung cancer cell lines and, accordingly, that TLR3 expression is associated with caspase-3 activation in adenocarcinoma NSCLC specimens, both evaluated by immunohistochemistry. Moreover, we showed that TLR3 expression on cancer cells contributes to activate the CD103+ lung dendritic cell subset, that is specifically associated with processing of antigens derived from apoptotic cells and their presentation to CD8+ T lymphocytes. These findings point to the relevant role of TLR3 expression on lung cancer cells and support the use of TLR3 agonists in NSCLC patients to re-activate local innate immune response.

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Dual Role of TLR3 in Inflammation and Cancer Cell Apoptosis

Cited by 10 publications

References 128 publications

Prevention of dsRNA‐induced interferon signaling by AGO1x is linked to breast cancer cell proliferation

Prevention of dsRNA‐induced interferon signaling by AGO1x is linked to breast cancer cell proliferation

Exploiting poly(I:C) to induce cancer cell apoptosis

TLR3 Expression Induces Apoptosis in Human Non-Small-Cell Lung Cancer

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