Natural compound Alternol actives multiple endoplasmic reticulum stress-responding pathways contributing to cell death.
Autor: | Liu W; Department of Urology, The University of Kansas Medical Center, Kansas City, KS, United States., He C; Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an, China., Li C; Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China., Ye S; Translational Research Laboratory for Urology, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, China., Zhao J; Department of Urology, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, China., Zhu C; Department of Urology, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, China., Wang X; Department of Urology, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, China., Ma Q; Translational Research Laboratory for Urology, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, China., Li B; Department of Urology, The University of Kansas Medical Center, Kansas City, KS, United States. |
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Jazyk: | angličtina |
Zdroj: | Frontiers in pharmacology [Front Pharmacol] 2024 May 20; Vol. 15, pp. 1397116. Date of Electronic Publication: 2024 May 20 (Print Publication: 2024). |
DOI: | 10.3389/fphar.2024.1397116 |
Abstrakt: | Background: Alternol is a small molecular compound isolated from the fermentation of a mutant fungus obtained from Taxus brevifolia bark. Our previous studies showed that Alternol treatment induced reactive oxygen species (ROS)-dependent immunogenic cell death. This study conducted a comprehensive investigation to explore the mechanisms involved in Alternol-induced immunogenic cell death. Methods: Prostate cancer PC-3, C4-2, and 22RV1 were used in this study. Alternol interaction with heat shock proteins (HSP) was determined using CETSA assay. Alternol-regulated ER stress proteins were assessed with Western blot assay. Extracellular adenosine triphosphate (ATP) was measured using ATPlite Luminescence Assay System. Results: Our results showed that Alternol interacted with multiple cellular chaperone proteins and increased their expression levels, including endoplasmic reticulum (ER) chaperone hypoxia up-regulated 1 (HYOU1) and heat shock protein 90 alpha family class B member 1 (HSP90AB1), as well as cytosolic chaperone heat shock protein family A member 8 (HSPA8). These data represented a potential cause of unfolded protein response (UPR) after Alternol treatment. Further investigation revealed that Alternol treatment triggered ROS-dependent (ER) stress responses via R-like ER kinase (PERK), inositol-requiring enzyme 1α (IRE1α). The double-stranded RNA-dependent protein kinase (PKR) but not activating transcription factor 6 (ATF6) cascades, leading to ATF-3/ATF-4 activation, C/EBP-homologous protein (CHOP) overexpression, and X-box binding protein XBP1 splicing induction. In addition, inhibition of these ER stress responses cascades blunted Alternol-induced extracellular adenosine triphosphate (ATP) release, one of the classical hallmarks of immunogenic cell death. Conclusion: Taken together, our data demonstrate that Alternol treatment triggered multiple ER stress cascades, leading to immunogenic cell death. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision. (Copyright © 2024 Liu, He, Li, Ye, Zhao, Zhu, Wang, Ma and Li.) |
Databáze: | MEDLINE |
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