Integrated control of cancer stemness by σ1 receptor in advanced prostate cancer

Cancer stem cells (CSCs) are pervasively present in human cancers and have a fundamental role in treatment failure and disease recurrence. Identifying critical elements that sustain the CSC phenotype may lead to novel strategies for cancer treatment. Here, we provide evidence of an essential link between the σ<sub>1</sub> receptor (σ<sub>1</sub>R), a ligand-regulated chaperone protein residing preferentially at the endoplasmic reticulum-mitochondria contact sites, and CSCs in castration-resistant prostate cancers (CRPCs). Integrating functional assays in multiple preclinical models with transcriptomic and proteomic data, we found that σ<sub>1</sub>R controls CSC self-renewal capacity and tumorigenic proficiency by coordinating mitochondrial dynamics and mitochondrial-nuclear signaling. Inhibiting σ<sub>1</sub>R with synthetic antagonists and RNA interference led to the progressive exhaustion and loss of tumorigenicity of the CSC progeny. Mechanistically, interfering with σ<sub>1</sub>R function disrupted mitochondria homeostasis and triggered β-catenin degradation. Examining clinical CRPC samples, we found a tight correlation between σ<sub>1</sub>R and mitochondrial gene expression. Furthermore, σ<sub>1</sub>R and β-catenin protein levels were highly correlated in prostate tumors with significant upregulation in metastatic CRPCs, sustaining a role of the σ<sub>1</sub>R-mitochondria-β-catenin axis in disease progression. This σ<sub>1</sub>R-centered axis is essential for preserving the self-renewal and tumorigenic capability of CSCs and represents a critical vulnerability exploitable for discovering novel CSC-directed therapies.

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Publication Details

Journal
Oncogene
Published
2025-09-02
DOI
https://doi.org/10.1038/s41388-025-03541-7
Primary Topic
Pharmacological Receptor Mechanisms and Effects
Type
article
Field-Weighted Citation Impact
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article

Integrated control of cancer stemness by σ1 receptor in advanced prostate cancer

Elisa Federici, Dheeraj Shinde, Matteo Pecoraro, Martina Marchetti‐Deschmann et al.
1 links
Oncogene
Pharmacological Receptor Mechanisms and Effects
article

Integrated control of cancer stemness by σ1 receptor in advanced prostate cancer

Elisa Federici, Dheeraj Shinde, Matteo Pecoraro, Martina Marchetti‐Deschmann, Catharina Holtschulte, Sabrina Pricl, Roger Geiger, Andrea Rinaldi, Bernhard Wünsch, Simone Mosole, Jessica Merulla, Marco Bolis, Carola Musumeci, Gianluca Civenni, Riccardo Valzelli, Erik Laurini, Alyssa Paganoni, Giada Sandrini, Giuseppina M. Carbone, Domenico Albino, Aleksandra Kokanovic, Carlo V. Catapano, Elisa Sorrenti, Arianna Vallerga, Tobias Winge
article en

Abstract

Cancer stem cells (CSCs) are pervasively present in human cancers and have a fundamental role in treatment failure and disease recurrence. Identifying critical elements that sustain the CSC phenotype may lead to novel strategies for cancer treatment. Here, we provide evidence of an essential link between the σ<sub>1</sub> receptor (σ<sub>1</sub>R), a ligand-regulated chaperone protein residing preferentially at the endoplasmic reticulum-mitochondria contact sites, and CSCs in castration-resistant prostate cancers (CRPCs). Integrating functional assays in multiple preclinical models with transcriptomic and proteomic data, we found that σ<sub>1</sub>R controls CSC self-renewal capacity and tumorigenic proficiency by coordinating mitochondrial dynamics and mitochondrial-nuclear signaling. Inhibiting σ<sub>1</sub>R with synthetic antagonists and RNA interference led to the progressive exhaustion and loss of tumorigenicity of the CSC progeny. Mechanistically, interfering with σ<sub>1</sub>R function disrupted mitochondria homeostasis and triggered β-catenin degradation. Examining clinical CRPC samples, we found a tight correlation between σ<sub>1</sub>R and mitochondrial gene expression. Furthermore, σ<sub>1</sub>R and β-catenin protein levels were highly correlated in prostate tumors with significant upregulation in metastatic CRPCs, sustaining a role of the σ<sub>1</sub>R-mitochondria-β-catenin axis in disease progression. This σ<sub>1</sub>R-centered axis is essential for preserving the self-renewal and tumorigenic capability of CSCs and represents a critical vulnerability exploitable for discovering novel CSC-directed therapies.

OncogeneVol. 44(42)
SIB Swiss Institute of Bioinformatics (CH), University of Trieste (IT), Mario Negri Institute for Pharmacological Research (IT), University of Münster (DE), Institute of Oncology Research (CH), Università della Svizzera italiana (CH)
National Science Foundation, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Krebsliga Schweiz
Openalex Percentile: Top 79%
Pharmacological Receptor Mechanisms and Effects
DOIOpen Access PDFOpenAlex
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