IRE1 Alpha/XBP1 Axis Sustains Primary Effusion Lymphoma Cell Survival by Promoting Cytokine Release and STAT3 Activation

Biomedicines

MariaAnele Romeo¹  Mara Cirone¹  MariaSaveria Gilardini Montani¹  Roberta Gonnella¹  Roberta Santarelli¹  Luisa Guttieri² 

[1] Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy;Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, 00161 Rome, Italy;

关键词: ER stress;    UPR;    IRE1 alpha;    XBP1;    STAT3;    cytokines;   

DOI  :  10.3390/biomedicines9020118

来源: DOAJ

【 摘 要 】

Primary Effusion Lymphoma (PEL) is a highly aggressive B cell lymphoma associated with Kaposi’s Sarcoma-associated Herpesvirus (KSHV). It is characterized by a high level of basal Endoplasmic Reticulum (ER) stress, Unfolded Protein Response (UPR) activation and constitutive phosphorylation of oncogenic pathways such as the Signal Transducer and activator of Transcription (STAT3). In this study, we found that the inositol requiring kinase (IRE) 1alpha/X-box binding protein (XBP1) axis of UPR plays a key role in the survival of PEL cells, while double stranded RNA-activated protein kinase-like ER kinase (PERK) and activating transcription factor (ATF) 6 slightly influence it, in correlation with the capacity of the IRE1alpha/XBP1 axis to induce the release of interleukin (IL)-6, IL-10 and Vascular-Endothelial Growth Factor (VEGF). Moreover, we found that IRE1alpha/XBP1 inhibition reduced STAT3 Tyr705 phosphorylation and induced a pro-survival autophagy in PEL cells. In conclusion, this study suggests that targeting the IRE1alpha/XBP1 axis represents a promising strategy against PEL cells and that the cytotoxic effect of this treatment may be potentiated by autophagy inhibition.

【 授权许可】

Unknown