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. 2022 Feb 23;41:75. doi: 10.1186/s13046-022-02284-7

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© The Author(s) 2022

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

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Fig. 7 — Mechanism of cisplatin MLN4924 combination action in MPM cells. MLN4924-non-responsive cells escape the lethal UPR because the low levels of UBE2M and SKP2, and the high activity of proteasome even in the presence of cisplatin prevents the accumulation of unfolded proteins and the consequent immunogenic cell death (ICD). By contrast, MLN4924-responsive cells had higher SKP2 levels and UBE2M activity, coupled with low proteasome activity when treated with cisplatin. The simultaneous block of SCF complex and proteasome enormously increases the accumulation of unfolded/ubiquitinated protein, triggering ER stress, exposure of calreticulin (CRT) on the cell surface, release of ATP and high mobile group B1 (HMGB1), activation of dendritic cells (DC) and CD8⁺T-cell against tumor, therefore inducing a canonical ICD. N: NEDD8.