4-Nerolidylcatechol binds to Derlin-1 and modulates endoplasmic reticulum stress markers of androgen-independent prostate cancer cells.

Authors

Antonielle Oliveira Cordeiro, Gabriela da Silva Guimarães, Paula Marynella Alves Pereira Lima, Hebréia Oliveira Almeida Souza, Mário Machado Martins, José Augusto Leoncio Gomide, Joyce Ferreira da Costa Guerra, Gislaine Gonçalves Rocha, Ademar Alves da Silva Filho, Nilson Nicolau-Júnior, Thaise Gonçalves Araújo

Published in

Chemico-biological interactions. Pages 112354. Sep 29, 2026. Epub Sep 29, 2026.

Abstract

Castration-resistant prostate cancer (CRPC) is a lethal disease characterized by androgen receptor-independent activation mechanisms that promote prolonged or unresolved endoplasmic reticulum (ER) stress. Consequently, these cells rely on the endoplasmic reticulum-associated degradation (ERAD) pathway, specifically Derlin-1, to maintain proteostasis under chronic stress, which makes this protein a significant therapeutic target. We previously demonstrated that 4-Nerolidylcatechol (4-NC), the main secondary metabolite of Piper umbellatum (capeba), downregulates the epithelial-mesenchymal transition in androgen-independent prostate cancer cells (PC-3). In this study, we aimed to evaluate the potential of 4-NC to interact with Derlin-1 and modulate redox status and ER stress markers using in silico and in vitro approaches. Docking simulations and 100-ns molecular dynamics predicted that 4-NC binds within the Derlin-1 retrotranslocation channel, establishing polar interactions with Arg85 and Thr88 and hydrophobic contacts with Val142, Met140, Ala152, and Leu155, thereby conferring conformational stability to the complex in silico. In PC-3 cells, 4-NC exhibited concentration-dependent cytotoxicity and antiproliferative selectivity, with IC₅₀ values of 39.2 μM in PC-3 and 86.7 μM in non-neoplastic PNT-2 cells (SRB assay; p < 0.05). Functional assays showed that 4-NC, at sub-cytotoxic concentrations, significantly increased intracellular reactive oxygen species levels, reduced glutathione levels by up to approximately 70%, enhanced lipid peroxidation, and progressively induced mitochondrial depolarization in PC-3 cells (p < 0.05). Consistently, 4-NC induced the expression of transcripts related to UPR/ERAD pathways (ATF4, BiP, EDEM, CHOP) and altered the proteome of treated PC-3 cells, indicating the activation of ER stress responses and a shift toward a pro-apoptotic transcriptional profile at higher concentrations. These findings highlight 4-NC as a promising natural compound for targeting the Derlin-1/ERAD axis, shedding light on mechanisms and promising targets not yet described in CRPC. Although previous reports demonstrated that 4-NC regulates the epithelial-mesenchymal transition in PC-3 cells, the present study identified, for the first time, Derlin-1 as a potential molecular target of 4-NC, highlighting the role of ER stress in CRPC.

PMID:
42810633
Bibliographic data and abstract were imported from PubMed on 30 Sep 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.