Secreted spermidine synthase reveals a paracrine role for PGC1α-induced growth suppression in prostate cancer

Prostate cancer is the fifth cause of death by cancer worldwide, second in incidence in the male population. The definition of the molecular basis of its development and the oncogenic signals driving lethality continue to be important objectives in prostate cancer research. Prior work from others and us has demonstrated that loss of PGC1α expression results in a metabolic, signaling and transcriptional reprogramming that supports the development of metastatic disease. However, we do not fully understand the spectrum of tumor suppressive effects regulated by this co-regulator. Here we show that PGC1α governs non-cell autonomous paracrine tumor suppression in prostate cancer. A systematic analysis of the transcriptional landscapes associated to PGC1α loss of expression revealed that PGC1α alters the expression of genes encoding for secreted proteins. Cell secretome studies corroborated that PGC1α-dependent ERRα regulation in prostate cancer cells suppresses the growth of tumor cells exposed to their conditioned media, independently of androgen receptor status. The integration of in vitro and in vivo secretomics data and genetic perturbation assays revealed spermidine synthase as a transcriptional target of PGC1α and mediator of the paracrine metabolic growth suppressive effect. Moreover, the activity of the regulatory axis PGC1α-ERRα-SRM was reflected in patients and had prognostic value. Altogether, this work provides unprecedented evidence of the non-cell autonomous suppressive role of PGC1α, which broadens the view of this co-regulator as a multifactorial tumor suppressor in prostate cancer.

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Publication Details

Journal
Cell Death and Disease
Published
2025-04-23
DOI
https://doi.org/10.1038/s41419-025-07639-4
Citations
2
Primary Topic
Polyamine Metabolism and Applications
Type
article
Field-Weighted Citation Impact
1.61

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article

Secreted spermidine synthase reveals a paracrine role for PGC1α-induced growth suppression in prostate cancer

Verónica Torrano, Ivana Heřmanová, Arkaitz Carracedo, Mikel Pujana-Vaquerizo et al.
2 citations
Cell Death and Disease
Polyamine Metabolism and Applications
1.61
article

Secreted spermidine synthase reveals a paracrine role for PGC1α-induced growth suppression in prostate cancer

Verónica Torrano, Ivana Heřmanová, Arkaitz Carracedo, Mikel Pujana-Vaquerizo, Félix Royo, Amaia Zabala‐Letona, Héctor Peinado, Lorea Valcárcel-Jiménez, Ariane Schaub-Clerigué, Edurne Berra, Juan Manuel Falcón‐Pérez, Benoît Lectez, Alice Macchia, Natalia Martín-Martín, James D. Sutherland, Mikel Azkargorta, Ianire Astobiza, Saioa Garcia‐Longarte, M. V. Sydorenko, Maider Fagoaga-Eugui, Ainara Pintor-Rial
article en
2 citations

Abstract

Prostate cancer is the fifth cause of death by cancer worldwide, second in incidence in the male population. The definition of the molecular basis of its development and the oncogenic signals driving lethality continue to be important objectives in prostate cancer research. Prior work from others and us has demonstrated that loss of PGC1α expression results in a metabolic, signaling and transcriptional reprogramming that supports the development of metastatic disease. However, we do not fully understand the spectrum of tumor suppressive effects regulated by this co-regulator. Here we show that PGC1α governs non-cell autonomous paracrine tumor suppression in prostate cancer. A systematic analysis of the transcriptional landscapes associated to PGC1α loss of expression revealed that PGC1α alters the expression of genes encoding for secreted proteins. Cell secretome studies corroborated that PGC1α-dependent ERRα regulation in prostate cancer cells suppresses the growth of tumor cells exposed to their conditioned media, independently of androgen receptor status. The integration of in vitro and in vivo secretomics data and genetic perturbation assays revealed spermidine synthase as a transcriptional target of PGC1α and mediator of the paracrine metabolic growth suppressive effect. Moreover, the activity of the regulatory axis PGC1α-ERRα-SRM was reflected in patients and had prognostic value. Altogether, this work provides unprecedented evidence of the non-cell autonomous suppressive role of PGC1α, which broadens the view of this co-regulator as a multifactorial tumor suppressor in prostate cancer.

Cell Death and DiseaseVol. 16(1)
Ikerbasque (ES), University of the Basque Country (ES), Spanish National Cancer Research Centre (ES), CIC bioGUNE (ES), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (ES), Centro de Investigación del Cáncer (ES), Centro de Investigación Biomédica en Red de Cáncer (ES)
Fundación BBVA, Department of Industry, Tourism and Trade, European Commission, Fundación Científica Asociación Española Contra el Cáncer, Eusko Jaurlaritza, Euskal Herriko Unibertsitatea, Ministerio de Ciencia e Innovación, Banco Bilbao Vizcaya Argentaria, Fundación Domingo Martínez, Horizon 2020 Framework Programme, Agencia Estatal de Investigación
Good health and well-being
Openalex Percentile: Top 18%
Polyamine Metabolism and Applications
1.61
DOIOpen Access PDFOpenAlex
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