Inositol hexaphosphate enhances chemotherapy by reversing senescence induced by persistently activated PERK and diphthamide modification of eEF2.

Autor: Xu B; Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, Xi'an 710038, China; Shaanxi Provincial Key Laboratory of Infection and Immune Disease, Shaanxi Provincial People's Hospital, Xi'an 710038, China., Jia Q; Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, Xi'an 710038, China; Shaanxi Provincial Key Laboratory of Infection and Immune Disease, Shaanxi Provincial People's Hospital, Xi'an 710038, China., Liao X; Department of Nutrition, First Affiliated Hospital of Xi'an JiaoTong University, Xi'an 710038, China., Fan T; Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, Xi'an 710038, China., Mou L; Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, Xi'an 710038, China., Song Y; Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, Xi'an 710038, China., Zhu C; Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, Xi'an 710038, China., Yang T; Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, Xi'an 710038, China; Shaanxi Provincial Key Laboratory of Infection and Immune Disease, Shaanxi Provincial People's Hospital, Xi'an 710038, China., Li Z; Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, Xi'an 710038, China., Wang M; Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, Xi'an 710038, China., Zhang Q; Department of General Surgery, Qilu Hospital, Shandong University, Jinan 250012, China. Electronic address: zqb-sd@163.com., Liang L; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. Electronic address: llknight115@163.com.
Jazyk: angličtina
Zdroj: Cancer letters [Cancer Lett] 2024 Feb 01; Vol. 582, pp. 216591. Date of Electronic Publication: 2023 Dec 12.
DOI: 10.1016/j.canlet.2023.216591
Abstrakt: Oxaliplatin is an important initial chemotherapy benefiting advanced-stage colorectal cancer patients. Frustratingly, acquired oxaliplatin resistance always occurs after sequential chemotherapy with diverse antineoplastic drugs. Therefore, an exploration of the mechanism of oxaliplatin resistance formation in-depth is urgently needed. We generated oxaliplatin-resistant colorectal cancer models by four representative compounds, and RNA-seq revealed that oxaliplatin resistance was mainly the result of cells' response to stimulus. Moreover, we proved persistent stimulus-induced endoplasmic reticulum stress (ERs) and associated cellular senescence were the core causes of oxaliplatin resistance. In addition, we screened diverse phytochemicals for ER inhibitors in silico, identifying inositol hexaphosphate (IP6), whose strong binding was confirmed by surface plasmon resonance. Finally, we confirmed the ability of IP6 to reverse colorectal cancer chemoresistance and investigated the mechanism of IP6 in the inhibition of diphthamide modification of eukaryotic elongation factor 2 (eEF2) and PERK activation. Our study demonstrated that oxaliplatin resistance contributed to cell senescence induced by persistently activated PERK and diphthamide modification of eEF2 levels, which were specifically reversed by combination therapy with IP6.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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