Shikonin improves the effectiveness of PD-1 blockade in colorectal cancer by enhancing immunogenicity via Hsp70 upregulation
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Published:2024-01-06
Issue:1
Volume:51
Page:
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ISSN:0301-4851
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Container-title:Molecular Biology Reports
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language:en
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Short-container-title:Mol Biol Rep
Author:
Chen Jinghua, Liu Jie, Liu Xiaolin, Wang Jun, Wang Xiumei, Ye Xin, Xie QiORCID, Liang Jing, Li Yan
Abstract
Abstract
Background
PD-1 blockade has shown impressive clinical outcomes in colorectal cancers patients with high microsatellite instability (MSI-H). However, the majority of patients with colorectal cancer who present low microsatellite instability (MSI-L) or stable microsatellites (MSS) show little response to PD-1 blockade therapy. Here, we have demonstrated that Shikonin (SK) could induce cell death of CT26 cells via classically programmed and immunogenic pathways.
Methods and results
SK promoted the membrane exposure of calreticulin and upregulated the expression of heat shock protein 70 (Hsp70). The upregulation of Hsp70 was dependent on ROS induced by SK and silencing of PKM2 in CT26 cells reverts ROS upregulation. Besides, SK synergizes with PD-1 blockade in CT26 tumor mice model, with the increase of intramural DC cells and CD8+ T cells. The expression of Hsp70 in tumor tissue was also increased in combinational SK plus αPD-1 therapy group.
Conclusions
Our study elucidated the potential role of ‘Shikonin-PKM2-ROS-Hsp70’ axis in the promotion of efficacy of PD-1 blockade in CRC treatments, providing a potential strategy and targets for improving the efficacy of PD-1 blockade in colorectal cancer.
Funder
Shandong Provincial Natural Science Foundation the Major Science and Technology Innovation Project of Shandong Province Traditional Chinese Medicine Science and Technology Development Plan of Shandong Province Shandong Provincial Qianfoshan Hospital
Publisher
Springer Science and Business Media LLC
Subject
Genetics,Molecular Biology,General Medicine
Reference37 articles.
1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A (2015) Global cancer statistics 2012. Cancer J Clin 65(2):87–108. https://doi.org/10.3322/caac.21262 2. Damato A, Bergamo F, Antonuzzo L, Nasti G, Iachetta F, Romagnani A, Gervasi E, Larocca M, Pinto C (2021) FOLFOXIRI/bevacizumab plus nivolumab as first-line treatment in metastatic colorectal cancer RAS/BRAF mutated: safety run-in of phase II NIVACOR trial. Front Oncol 11:766500. https://doi.org/10.3389/fonc.2021.766500 3. Provenzale D, Ness RM, Llor X, Weiss JM, Abbadessa B, Cooper G, Early DS, Friedman M, Giardiello FM, Glaser K, Gurudu S, Halverson AL, Issaka R, Jain R, Kanth P, Kidambi T, Lazenby AJ, Maguire L, Markowitz AJ, May FP, Ogba N (2020) NCCN guidelines insights: colorectal cancer screening, version 2.2020. J Natl Compr Cancer Netw 18(10):1312–1320. https://doi.org/10.6004/jnccn.2020.0048 4. Ascierto PA, Del Vecchio M, Mandalá M, Gogas H, Arance AM, Dalle S, Cowey CL, Schenker M, Grob JJ, Chiarion-Sileni V, Márquez-Rodas I, Butler MO, Maio M, Middleton MR, de la Cruz-Merino L, Arenberger P, Atkinson V, Hill A, Fecher LA, Millward M, Weber J (2020) Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial. Lancet Oncol 21(11):1465–1477. https://doi.org/10.1016/S1470-2045(20)30494-0 5. Mok TSK, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, Castro G Jr, Srimuninnimit V, Laktionov KK, Bondarenko I, Kubota K, Lubiniecki GM, Zhang J, Kush D, Lopes G, KEYNOTE-042 Investigators (2019) Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet 393(10183):1819–1830. https://doi.org/10.1016/S0140-6736(18)32409-7
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