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KSHV dysregulates bulk macroautophagy, mitophagy and UPR to promote endothelial to mesenchymal transition and CCL2 release, key events in viral‐driven sarcomagenesis
Author(s) -
Santarelli Roberta,
Arteni Ana Maria Brindusa,
Gilardini Montani Maria Saveria,
Romeo Maria Anele,
Gaeta Aurelia,
Gonnella Roberta,
Faggioni Alberto,
Cirone Mara
Publication year - 2020
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.33163
Subject(s) - microbiology and biotechnology , pi3k/akt/mtor pathway , mitophagy , epithelial–mesenchymal transition , angiogenesis , mesenchymal stem cell , ccl2 , autophagy , reprogramming , unfolded protein response , mechanistic target of rapamycin , chemokine , inflammation , biology , chemistry , signal transduction , cancer research , immunology , endoplasmic reticulum , transition (genetics) , cell , genetics , apoptosis , gene
Kaposi's sarcoma‐associated herpesvirus (KSHV) is the causative agent of KS, an aggressive neoplasm that mainly occurs in immune‐compromised patients. Spindle cells represent the main feature of this aggressive malignancy and arise from KSHV‐infected endothelial cells undergoing endothelial to mesenchymal transition (EndMT), which changes their cytoskeletal composition and organization. As in epithelial to mesenchymal transition (EMT), EndMT is driven by transcription factors such as SNAI1 and ZEB1 and implies a cellular reprogramming mechanism regulated by several molecular pathways, particularly PI3K/AKT/MTOR. Here we found that KSHV activated MTOR and its targets 4EBP1 and ULK1 and reduced bulk macroautophagy and mitophagy to promote EndMT, activate ER stress/unfolded protein response (UPR), and increase the release of the pro‐angiogenic and pro‐inflammatory chemokine CCL2 by HUVEC cells. Our study suggests that the manipulation of macroautophagy, mitophagy and UPR and the interplay between the three could be a promising strategy to counteract EndMT, angiogenesis and inflammation, the key events of KSHV‐driven sarcomagenesis.