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Glutaminolysis is a metabolic route essential for survival and growth of prostate cancer cells and a target of 5α-dihydrotestosterone regulation

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Abstract

Purpose

Resistance to androgen-deprivation therapies and progression to so-called castrate-resistant prostate cancer (CRPC) remain challenges in prostate cancer (PCa) management and treatment. Among other alterations, CRPC has been associated with metabolic reprogramming driven by androgens. Here, we investigated the role of androgens in regulating glutaminolysis in PCa cells and determined the relevance of this metabolic route in controlling the survival and growth of androgen-sensitive (LNCaP) and CRPC (DU145 and PC3) cells.

Methods

PCa cells (LNCaP, DU145 and PC3) and 3-month old rats were treated with 5α-dihydrotestosterone (DHT). Alternatively, LNCaP cells were exposed to the glutaminase inhibitor BPTES, alone or in combination with the anti-androgen bicalutamide. Biochemical, Western blot and extracellular flux assays were used to evaluate the viability, proliferation, migration and metabolism of PCa cells in response to DHT treatment or glutaminase inhibition.

Results

We found that DHT up-regulated the expression of the glutamine transporter ASCT2 and glutaminase, both in vitro in LNCaP cells and in vivo in rat prostate cells. BPTES diminished the viability and migration of PCa cells, while increasing caspase-3 activity. CRPC cells were found to be more dependent on glutamine and more sensitive to glutaminase inhibition. BPTES and bicalutamide co-treatment had an additive effect on suppressing LNCaP cell viability. Finally, we found that inhibition of glutaminolysis differentially affected glycolysis and lipid metabolism in both androgen-sensitive and CRPC cells.

Conclusion

Our data reveal glutaminolysis as a central metabolic route controlling PCa cell fate and highlight the relevance of targeting glutaminase for CRPC treatment.

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Acknowledgments

This work was supported by FEDER funds through the POCI - COMPETE 2020 - Operational Programme Competitiveness and Internationalization in Axis I -Strengthening research, technological development and innovation (Projects No. 007491 and 029114) and National Funds by the FCT-Foundation for Science and Technology (Project UID/Multi/00709/2013). Cardoso H. J. and Figueira M.I. are recipients of FCT fellowships SFRH/BD/111351/2015 and SFRH/BD/104671/2014, respectively. P.A.M. is funded by an FCT Investigator contract from the Foundation for Science and Technology (FCT), Portugal (Ref: IF/00614/2014) and an FCT exploratory grant, Ref: IF/00614/2014/CP12340006. CBMR is financed by an FCT Research Center grant.

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  1. CICS-UBI, Centro de Investigação em Ciências da Saúde, Universidade da Beira Interior, Av. Infante D. Henrique, 6200-506, Covilhã, Portugal

    Henrique J. Cardoso, Marília I. Figueira, Cátia V. Vaz, Tiago M. A. Carvalho, Luís A. Brás & Sílvia Socorro

  2. Centre for Biomedical Research (CBMR), Campus of Gambelas, University of Algarve, Faro, Portugal

    Henrique J. Cardoso & Patrícia A. Madureira

  3. Brain Tumour Research Centre of Excellence, Institute of Biomedical and Biomolecular Sciences, University of Portsmouth, Portsmouth, UK

    Patrícia A. Madureira

  4. CNC – Center for Neuroscience and Cell Biology, UC-Biotech, University of Coimbra, Biocant Park, Cantanhede, Portugal

    Paulo J. Oliveira & Vilma A. Sardão

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  1. Henrique J. Cardoso
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Cardoso, H.J., Figueira, M.I., Vaz, C.V. et al. Glutaminolysis is a metabolic route essential for survival and growth of prostate cancer cells and a target of 5α-dihydrotestosterone regulation. Cell Oncol. 44, 385–403 (2021). https://doi.org/10.1007/s13402-020-00575-9

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