The estrogen signaling pathway reprograms prostate cancer cell metabolism and supports proliferation and disease progression
Camille Lafront, Lucas Germain, Gabriel H. Campolina-Silva, Cindy Weidmann, Line Berthiaume, Hélène Hovington, Hervé Brisson, Cynthia Jobin, Lilianne Frégeau-Proulx, Raul Cotau, Kevin Gonthier, Aurélie Lacouture, Patrick Caron, Claire Ménard, Chantal Atallah, Julie Riopel, Éva Latulippe, Alain Bergeron, Paul Toren, Chantal Guillemette, Martin Pelletier, Yves Fradet, Clémence Belleannée, Frédéric Pouliot, Louis Lacombe, Éric Lévesque, Étienne Audet-Walsh
Camille Lafront, Lucas Germain, Gabriel H. Campolina-Silva, Cindy Weidmann, Line Berthiaume, Hélène Hovington, Hervé Brisson, Cynthia Jobin, Lilianne Frégeau-Proulx, Raul Cotau, Kevin Gonthier, Aurélie Lacouture, Patrick Caron, Claire Ménard, Chantal Atallah, Julie Riopel, Éva Latulippe, Alain Bergeron, Paul Toren, Chantal Guillemette, Martin Pelletier, Yves Fradet, Clémence Belleannée, Frédéric Pouliot, Louis Lacombe, Éric Lévesque, Étienne Audet-Walsh
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Research Article Endocrinology Oncology

The estrogen signaling pathway reprograms prostate cancer cell metabolism and supports proliferation and disease progression

Abstract

Just like the androgen receptor (AR), the estrogen receptor α (ERα) is expressed in the prostate and is thought to influence prostate cancer (PCa) biology. Yet the incomplete understanding of ERα functions in PCa hinders our ability to fully comprehend its clinical relevance and restricts the repurposing of estrogen-targeted therapies for the treatment of this disease. Using 2 human PCa tissue microarray cohorts, we first demonstrate that nuclear ERα expression was heterogeneous among patients, being detected in only half of the tumors. Positive nuclear ERα levels were correlated with disease recurrence, progression to metastatic PCa, and patient survival. Using in vitro and in vivo models of the normal prostate and PCa, bulk and single-cell RNA-Seq analyses revealed that estrogens partially mimicked the androgen transcriptional response and activated specific biological pathways linked to proliferation and metabolism. Bioenergetic flux assays and metabolomics confirmed the regulation of cancer metabolism by estrogens, supporting proliferation. Using cancer cell lines and patient-derived organoids, selective estrogen receptor modulators, a pure anti-estrogen, and genetic approaches impaired cancer cell proliferation and growth in an ERα-dependent manner. Overall, our study revealed that, when expressed, ERα functionally reprogrammed PCa metabolism, was associated with disease progression, and could be targeted for therapeutic purposes.

Authors

Camille Lafront, Lucas Germain, Gabriel H. Campolina-Silva, Cindy Weidmann, Line Berthiaume, Hélène Hovington, Hervé Brisson, Cynthia Jobin, Lilianne Frégeau-Proulx, Raul Cotau, Kevin Gonthier, Aurélie Lacouture, Patrick Caron, Claire Ménard, Chantal Atallah, Julie Riopel, Éva Latulippe, Alain Bergeron, Paul Toren, Chantal Guillemette, Martin Pelletier, Yves Fradet, Clémence Belleannée, Frédéric Pouliot, Louis Lacombe, Éric Lévesque, Étienne Audet-Walsh

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Figure 5

ERα activation induces cancer cell metabolism, notably by promoting glucose consumption and usage.

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ERα activation induces cancer cell metabolism, notably by promoting gluc...
(A) Schematic overview of glucose metabolism through glycolysis to allow pyruvate synthesis, which can then fuel the mitochondrial TCA cycle for respiration. Note that not all enzymatic reactions are shown (dashed lines symbolize intermediate steps). αKG, α-ketoglutarate; Succ., succinate; Fum., fumarate; Oxalo., oxaloacetate. (B and C) Quantification of lactate (B), alanine (B), and TCA cycle intermediates (C) in VCaP cells following 72 hours of treatment with E2 or the synthetic androgen R1881 by gas chromatography–mass spectrometry (GC-MS). (D and E) Quantification of 13C incorporation from 13C-glucose in lactate and alanine (D) and TCA cycle intermediates (E) in VCaP cells following 72 hours of treatment with E2 or R1881. 13C-glucose allowed the enrichment of a heavier isotopomer with a mass of plus 3 (m+3) for lactate and alanine and a mass of plus 2 (m+2) for citrate, succinate, and malate if it feeds the TCA cycle. (F) Changes in VCaP cell numbers following 168 hours of treatment with either E2, the inhibitor of mitochondrial respiration metformin (Met), or both (Met + E2). The changes in cell numbers were normalized in percentages according to the control treatment. Results are shown as the mean ± SEM of 2 independent experiments (n = 16/treatment group). (G) Quantification of amino acids connected to energy synthesis pathways in VCaP cells following 72 hours of treatment with E2 or R1881 by GC-MS. For B–E and G, results are shown as the mean ± SEM of 1 representative experiment (n = 5/conditions) of 3 independent experiments. (H) Western blot of the mTOR signaling pathway with phosphorylation of downstream targets (S6 and S6K) following hormone treatment. α-Tubulin was used as a loading control. *P < 0.05, **P < 0.01, and ***P < 0.001, by 1-way ANOVA, respective to control conditions or as indicated. For D and E, P values are only shown for metabolites with 13C labeling. #P < 0.10 (G).