CD95L Inhibition Impacts Gemcitabine-Mediated Effects and Non-Apoptotic Signaling of TNF-α and TRAIL in Pancreatic Tumor Cells

Cancers

Freya Goumas¹  Jan-Hendrik Egberts¹  Khalid Rashid²  Christian Röder²  Holger Kalthoff² 

[1] Department of General, Visceral-, Thoracic-, Transplantation- and Paediatric Surgery, University Medical Centre Schleswig-Holstein (UKSH), Campus Kiel, 24105 Kiel, Germany;Institute for Experimental Cancer Research, University Medical Centre Schleswig-Holstein (UKSH), Campus Kiel, 24105 Kiel, Germany;

关键词: gemcitabine;    death ligands;    chemoresistance;    PDAC;    metastasis;   

DOI  :  10.3390/cancers13215458

来源: DOAJ

【 摘 要 】

Despite the potential apoptotic functions, the CD95/CD95L system can stimulate survival as well as pro-inflammatory signaling, particularly through the activation of NFκB. This holds true for the TNF/TNFR and the TRAIL/TRAILR systems. Thus, signaling pathways of these three death ligands converge, yet the specific impact of the CD95/CD95L system in this crosstalk has not been well studied. In this study, we show that gemcitabine stimulates the expression of pro-inflammatory cytokines, such as IL6 and IL8, under the influence of the CD95/CD95L system and the pharmacological inhibitor, sCD95Fc, substantially reduced the expression in two PDAC cell lines, PancTuI-luc and A818-4. The stem cell phenotype was reduced when induced upon gemcitabine as well by sCD95Fc. Moreover, TNF-α as well as TRAIL up-regulate the expression of CD95 and CD95L in both cell lines. Conversely, we detected a significant inhibitory effect of sCD95Fc on the expression of both IL8 and IL6 induced upon TNF-α and TRAIL stimulation. In vivo, CD95L inhibition reduced xeno-transplanted recurrent PDAC growth. Thus, our findings indicate that inhibition of CD95 signaling altered the chemotherapeutic effects of gemcitabine, not only by suppressing the pro-inflammatory responses that arose from the CD95L-positive tumor cells but also from the TNF-α and TRAIL signaling in a bi-lateral crosstalk manner.

【 授权许可】

Unknown