MYC is a regulator of androgen receptor inhibition-induced metabolic requirements in prostate cancer

Preston D. Crowell; Jenna M. Giafaglione; Anthony E. Jones; Nicholas M. Nunley; Takao Hashimoto; Amelie M.L. Delcourt; Anton Petcherski; Raag Agrawal; Matthew J. Bernard; Johnny A. Diaz; Kylie Y. Heering; Rong Rong Huang; Jin Yih Low; Nedas Matulionis; Nora M. Navone; Huihui Ye; Amina Zoubeidi; Heather R. Christofk; Matthew B. Rettig; Robert E. Reiter; Michael C. Haffner; Paul C. Boutros; Orian S. Shirihai; Ajit S. Divakaruni; Andrew S. Goldstein

doi:10.1016/j.celrep.2023.113221

MYC is a regulator of androgen receptor inhibition-induced metabolic requirements in prostate cancer

Preston D. Crowell, Jenna M. Giafaglione, Anthony E. Jones, Nicholas M. Nunley, Takao Hashimoto, Amelie M.L. Delcourt, Anton Petcherski, Raag Agrawal, Matthew J. Bernard, Johnny A. Diaz, Kylie Y. Heering, Rong Rong Huang, Jin Yih Low, Nedas Matulionis, Nora M. Navone, Huihui Ye, Amina Zoubeidi, Heather R. Christofk, Matthew B. Rettig, Robert E. ReiterMichael C. Haffner, Paul C. Boutros, Orian S. Shirihai, Ajit S. Divakaruni, Andrew S. Goldstein

Genitourinary Medical Oncology

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

Advanced prostate cancers are treated with therapies targeting the androgen receptor (AR) signaling pathway. While many tumors initially respond to AR inhibition, nearly all develop resistance. It is critical to understand how prostate tumor cells respond to AR inhibition in order to exploit therapy-induced phenotypes prior to the outgrowth of treatment-resistant disease. Here, we comprehensively characterize the effects of AR blockade on prostate cancer metabolism using transcriptomics, metabolomics, and bioenergetics approaches. The metabolic response to AR inhibition is defined by reduced glycolysis, robust elongation of mitochondria, and increased reliance on mitochondrial oxidative metabolism. We establish DRP1 activity and MYC signaling as mediators of AR-blockade-induced metabolic phenotypes. Rescuing DRP1 phosphorylation after AR inhibition restores mitochondrial fission, while rescuing MYC restores glycolytic activity and prevents sensitivity to complex I inhibition. Our study provides insight into the regulation of treatment-induced metabolic phenotypes and vulnerabilities in prostate cancer.

Original language	English (US)
Article number	113221
Journal	Cell Reports
Volume	42
Issue number	10
DOIs	https://doi.org/10.1016/j.celrep.2023.113221
State	Published - Oct 31 2023

Keywords

CP: Cancer
CP: Metabolism

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2023.113221

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Crowell, P. D., Giafaglione, J. M., Jones, A. E., Nunley, N. M., Hashimoto, T., Delcourt, A. M. L., Petcherski, A., Agrawal, R., Bernard, M. J., Diaz, J. A., Heering, K. Y., Huang, R. R., Low, J. Y., Matulionis, N., Navone, N. M., Ye, H., Zoubeidi, A., Christofk, H. R., Rettig, M. B., ... Goldstein, A. S. (2023). MYC is a regulator of androgen receptor inhibition-induced metabolic requirements in prostate cancer. Cell Reports, 42(10), Article 113221. https://doi.org/10.1016/j.celrep.2023.113221

Crowell, PD, Giafaglione, JM, Jones, AE, Nunley, NM, Hashimoto, T, Delcourt, AML, Petcherski, A, Agrawal, R, Bernard, MJ, Diaz, JA, Heering, KY, Huang, RR, Low, JY, Matulionis, N, Navone, NM, Ye, H, Zoubeidi, A, Christofk, HR, Rettig, MB, Reiter, RE, Haffner, MC, Boutros, PC, Shirihai, OS, Divakaruni, AS & Goldstein, AS 2023, 'MYC is a regulator of androgen receptor inhibition-induced metabolic requirements in prostate cancer', Cell Reports, vol. 42, no. 10, 113221. https://doi.org/10.1016/j.celrep.2023.113221

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title = "MYC is a regulator of androgen receptor inhibition-induced metabolic requirements in prostate cancer",

abstract = "Advanced prostate cancers are treated with therapies targeting the androgen receptor (AR) signaling pathway. While many tumors initially respond to AR inhibition, nearly all develop resistance. It is critical to understand how prostate tumor cells respond to AR inhibition in order to exploit therapy-induced phenotypes prior to the outgrowth of treatment-resistant disease. Here, we comprehensively characterize the effects of AR blockade on prostate cancer metabolism using transcriptomics, metabolomics, and bioenergetics approaches. The metabolic response to AR inhibition is defined by reduced glycolysis, robust elongation of mitochondria, and increased reliance on mitochondrial oxidative metabolism. We establish DRP1 activity and MYC signaling as mediators of AR-blockade-induced metabolic phenotypes. Rescuing DRP1 phosphorylation after AR inhibition restores mitochondrial fission, while rescuing MYC restores glycolytic activity and prevents sensitivity to complex I inhibition. Our study provides insight into the regulation of treatment-induced metabolic phenotypes and vulnerabilities in prostate cancer.",

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AU - Crowell, Preston D.

AU - Giafaglione, Jenna M.

AU - Jones, Anthony E.

AU - Nunley, Nicholas M.

AU - Hashimoto, Takao

AU - Delcourt, Amelie M.L.

AU - Petcherski, Anton

AU - Agrawal, Raag

AU - Bernard, Matthew J.

AU - Diaz, Johnny A.

AU - Heering, Kylie Y.

AU - Huang, Rong Rong

AU - Low, Jin Yih

AU - Matulionis, Nedas

AU - Navone, Nora M.

AU - Ye, Huihui

AU - Zoubeidi, Amina

AU - Christofk, Heather R.

AU - Rettig, Matthew B.

AU - Reiter, Robert E.

AU - Haffner, Michael C.

AU - Boutros, Paul C.

AU - Shirihai, Orian S.

AU - Divakaruni, Ajit S.

AU - Goldstein, Andrew S.

PY - 2023/10/31

Y1 - 2023/10/31

N2 - Advanced prostate cancers are treated with therapies targeting the androgen receptor (AR) signaling pathway. While many tumors initially respond to AR inhibition, nearly all develop resistance. It is critical to understand how prostate tumor cells respond to AR inhibition in order to exploit therapy-induced phenotypes prior to the outgrowth of treatment-resistant disease. Here, we comprehensively characterize the effects of AR blockade on prostate cancer metabolism using transcriptomics, metabolomics, and bioenergetics approaches. The metabolic response to AR inhibition is defined by reduced glycolysis, robust elongation of mitochondria, and increased reliance on mitochondrial oxidative metabolism. We establish DRP1 activity and MYC signaling as mediators of AR-blockade-induced metabolic phenotypes. Rescuing DRP1 phosphorylation after AR inhibition restores mitochondrial fission, while rescuing MYC restores glycolytic activity and prevents sensitivity to complex I inhibition. Our study provides insight into the regulation of treatment-induced metabolic phenotypes and vulnerabilities in prostate cancer.

AB - Advanced prostate cancers are treated with therapies targeting the androgen receptor (AR) signaling pathway. While many tumors initially respond to AR inhibition, nearly all develop resistance. It is critical to understand how prostate tumor cells respond to AR inhibition in order to exploit therapy-induced phenotypes prior to the outgrowth of treatment-resistant disease. Here, we comprehensively characterize the effects of AR blockade on prostate cancer metabolism using transcriptomics, metabolomics, and bioenergetics approaches. The metabolic response to AR inhibition is defined by reduced glycolysis, robust elongation of mitochondria, and increased reliance on mitochondrial oxidative metabolism. We establish DRP1 activity and MYC signaling as mediators of AR-blockade-induced metabolic phenotypes. Rescuing DRP1 phosphorylation after AR inhibition restores mitochondrial fission, while rescuing MYC restores glycolytic activity and prevents sensitivity to complex I inhibition. Our study provides insight into the regulation of treatment-induced metabolic phenotypes and vulnerabilities in prostate cancer.

KW - CP: Cancer

KW - CP: Metabolism

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MYC is a regulator of androgen receptor inhibition-induced metabolic requirements in prostate cancer

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Keywords

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