TY - JOUR
T1 - TRAIL receptors promote constitutive and inducible IL-8 secretion in non-small cell lung carcinoma
AU - Favaro, Francesca
AU - Luciano-Mateo, Fedra
AU - Moreno-Caceres, Joaquim
AU - Hernández-Madrigal, Miguel
AU - Both, Demi
AU - Montironi, Chiara
AU - Püschel, Franziska
AU - Nadal, Ernest
AU - Eldering, Eric
AU - Muñoz-Pinedo, Cristina
N1 - Funding Information: We thank CERCA Programme/Generalitat de Catalunya for institutional support. This study has been funded by Ministerio de Ciencia e Innovación, which is part of Agencia Estatal de Investigación (AEI), through the Generación de Conocimiento grant number PID2019-107213GB-I00 / DOI: 10.13039/501100011033 and BFU2016-78154-R (co-funded by FEDER). We have been funded through EU’s H2020 Research and Innovation Programme under the Marie Skłodowska-Curie Grant Agreement 766214 (META-CAN); and La Marató de TV3 project number 201929-30. Funding by ISCIII: grants PI18/00920 and PI21/00789 to EN (co-funded by FEDER) and FL-M CD20/00191 (Co-funded by European Social Fund). Publisher Copyright: © 2022, The Author(s).
PY - 2022/12/1
Y1 - 2022/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85144129413&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41419-022-05495-0
DO - https://doi.org/10.1038/s41419-022-05495-0
M3 - Article
C2 - 36522309
SN - 2041-4889
VL - 13
JO - Cell Death & Disease
JF - Cell Death & Disease
IS - 12
M1 - 1046
ER -