Modulating Tumor Promotion by Targeting Inflammation and Endoplasmic Reticulum Stress

Abstract

<strong>Background:</strong> Inflammation and ER stress are two prominent hallmarks of tumors, both exhibiting distinct dual roles in tumor promotion. The duration and intensity of inflammation and ER stress can drive divergent, or even opposite outcomes in tumor development. However, evolving tumors usually adapt and escape from inflammation and ER stress by forming delicate balances between them. Disrupting the balances by modulating inflammation and ER stress can impair this adapbility and induce tumor cell death.<br /> <strong>Purposes:</strong> This dissertation aims to illustrate the potential and mechanisms of regulating inflammation and ER stress in tumor treatment.<br /> Methods: We confirmed the derivation of pro-inflammatory cytokines from M1 macrophages, and illustrated the roles of pro-inflammatory cytokines in enhancing the cytotoxicity of CIK cells against MM and its mechanisms using flow cytometry. For the investigations on ER stress, we demonstrated the expression profile of ERO1L and a bidirection regulatory loop between ERO1L and ER stress in CRC by RT-qPCR and western-blotting. Furthermore, We elucidated the regulatory role of ERO1L on autophagy and apoptosis in tumour cells by flow cytometry, and resolved the responsible signalling pathways.<br /> <strong>Results:</strong> We found that M1 macrophages produced high levels of pro-inflammatory cytokines, including TNF-&alpha;, IL-1β, and IL-6. Pro-inflammatory cytokines enhanced the cytotoxicity of CIK cells towards MM cells by augmenting the expression of killing-dependent MICA/B. For ER stress, we revealed that ERO1L was overexpressed in CRC and found a negative regulatory feedback between ER stress and ERO1L. Inhibition of ERO1L induced apoptosis and autophagy via the induction of ER stress and the ERK1/2 pathway. In addtion, combining ERO1L inhibition with other ER stress-inducing agents showed a synergistic effect in CRC treatment.<br /> <strong>Conclusions:</strong> M1 macrophage-derived pro-inflammatory cytokines reinforce the cytotoxicity of CIK cells agianst MM cells by up-regulating the MICA/B-NKG2D axis. Inhibition of ERO1L mediates apoptosis and autophagy via the induction of ER stress in CRC.