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

Cell Rep. 2023 Oct 31;42(10):113221. doi: 10.1016/j.celrep.2023.113221. Epub 2023 Oct 9.

Authors

Preston D Crowell¹, Jenna M Giafaglione¹, Anthony E Jones², Nicholas M Nunley³, Takao Hashimoto³, Amelie M L Delcourt³, Anton Petcherski⁴, Raag Agrawal⁵, Matthew J Bernard¹, Johnny A Diaz³, Kylie Y Heering³, Rong Rong Huang⁶, Jin-Yih Low⁷, Nedas Matulionis⁸, Nora M Navone⁹, Huihui Ye⁶, Amina Zoubeidi¹⁰, Heather R Christofk¹¹, Matthew B Rettig¹², Robert E Reiter¹², Michael C Haffner¹³, Paul C Boutros¹⁴, Orian S Shirihai¹⁵, Ajit S Divakaruni², Andrew S Goldstein¹⁶

Affiliations

¹ Molecular Biology Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA 90095, USA.
² Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁴ Division of Endocrinology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁵ Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁶ Department of Pathology & Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁷ Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
⁸ Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁹ Department of GU Medical Oncology, MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁰ Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada; Vancouver Prostate Centre, Vancouver, BC, Canada.
¹¹ Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Stem Cell Research Center, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹² Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹³ Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA.
¹⁴ Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Institute for Precision Health, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹⁵ Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Division of Endocrinology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Clinical Biochemistry, School of Medicine, Ben Gurion University of The Negev, Beer-Sheva, Israel.
¹⁶ Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Stem Cell Research Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: agoldstein@mednet.ucla.edu.

PMID: 37815914
DOI: 10.1016/j.celrep.2023.113221

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.

Keywords: CP: Cancer; CP: Metabolism.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Androgens / metabolism
Cell Line, Tumor
Humans
Male
Prostatic Neoplasms* / genetics
Prostatic Neoplasms, Castration-Resistant* / genetics
Proto-Oncogene Proteins c-myc / genetics
Proto-Oncogene Proteins c-myc / metabolism
Receptors, Androgen / drug effects
Receptors, Androgen / metabolism
Signal Transduction

Substances

Androgens
Proto-Oncogene Proteins c-myc
Receptors, Androgen

Abstract

Publication types

MeSH terms

Substances

Grants and funding