TRAIL receptors promote constitutive and inducible IL-8 secretion in non-small cell lung carcinoma

Abstract

Interleukin-8 (IL-8/CXCL8) is a pro-angiogenic and pro-inflammatory chemokine that plays a role in cancer development. Non-small cell lung carcinoma (NSCLC) produces high amounts of IL-8, which is associated with poor prognosis and resistance to chemo-radio and immunotherapy. However, the signaling pathways that lead to IL-8 production in NSCLC are unresolved. Here, we show that expression and release of IL-8 are regulated autonomously by TRAIL death receptors in several squamous and adenocarcinoma NSCLC cell lines. NSCLC constitutively secrete IL-8, which could be further enhanced by glucose withdrawal or by treatment with TRAIL or TNFα. In A549 cells, constitutive and inducible IL-8 production was dependent on NF-κB and MEK/ERK MAP Kinases. DR4 and DR5, known regulators of these signaling pathways, participated in constitutive and glucose deprivation-induced IL-8 secretion. These receptors were mainly located intracellularly. While DR4 signaled through the NF-κB pathway, DR4 and DR5 both regulated the ERK-MAPK and Akt pathways. FADD, caspase-8, RIPK1, and TRADD also regulated IL-8. Analysis of mRNA expression data from patients indicated that IL-8 transcripts correlated with TRAIL, DR4, and DR5 expression levels. Furthermore, TRAIL receptor expression levels also correlated with markers of angiogenesis and neutrophil infiltration in lung squamous carcinoma and adenocarcinoma. Collectively, these data suggest that TRAIL receptor signaling contributes to a pro-tumorigenic inflammatory signature associated with NSCLC.

TNF-Related Apoptosis-Inducing Ligand: Non-Apoptotic Signalling

“…Yet, as was demonstrated more than 10 years ago by Azijli and co-workers, in the TRAIL-resistant cancer cell line A549, TRAIL induces, in addition to NF-κB, the phosphorylation of a large number of substrates associated with activation of the P38, ERK1/2, JNK1, Src, AKT, Raf1 and ROCK [ 364 ]. While the implication of TRADD for TRAIL signalling is less investigated, TRADD was found to afford protection against TRAIL-induced apoptosis [ 355 , 365 , 366 ], but more interestingly TRADD was suggested to play an important role in the secondary complex to induces IL-8 secretion in NSCLC, under TRAIL treatment [ 367 ]. Furthermore, TRADD and RIPK1 redundantly mediate proinflammatory signalling in response to TRAIL in human ovarian HeLa metastatic cell line [ 354 ].…”

Modulation of fracture healing by senescence-associated secretory phenotype (SASP): a narrative review of the current literature

“…The activated cGAs generate a second messenger ring nucleotide (cGAMP) that binds to the stimulator of interferon genes (STING) and promotes the aggregation of Sting with TANK-binding kinase 1(TBK 1) and IκB kinases. Therefore, interferon regulatory factor 3(IRF3) and NF-κB are activated, respectively, resulting in the production of type I interferon and SASP factors (such as IL-6, IL-8, IL-1 β, and MMP-12) [ 7 , 40 , 41 ].…”

Targeted therapy for non‐small‐cell lung cancer: New insights into regulated cell death combined with immunotherapy

“…Both DR4 and DR5 control the ERK–MAPK and Akt pathways, and DR4 mediates its effects through the NF‐kB pathway. FADD, caspase‐8, RIPK1, and TRADD also mediate IL‐8 secretion 25 . Therefore, combination therapy with immunotherapy and small‐molecule compounds targeting apoptosis may benefit NSCLC treatment.…”

“…FADD, caspase-8, RIPK1, and TRADD also mediate IL-8 secretion. 25 Therefore, combination therapy with immunotherapy and small-molecule compounds targeting apoptosis may benefit NSCLC treatment. However, no relevant research has yet been published.…”

“…Since p53 mutations are prevalent in tumors, targeting p53 represents a promising anticancer strategy (Figure2) 68. Shikonin (SHK)(25) is a naphthoquinone pigment from the root of Lithospermum erythrorhizon that inhibits the growth of various types of cancer cells in vitro. The proliferation of A549 and PC-9 cells decreased after treatment with SHK in a dosedependent manner, with IC 50 values of 1.221 ± 0.059 μM and 1.334 ± 0.114 μM, respectively.…”