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

被引：11

作者：

Crowell, Preston D. ^{[1
]}

Giafaglione, Jenna M. ^{[1
]}

Jones, Anthony E. ^{[2
]}

Nunley, Nicholas M. ^{[3
]}

Hashimoto, Takao ^{[3
]}

Delcourt, Amelie M. L. ^{[3
]}

Petcherski, Anton ^{[4
]}

Agrawal, Raag ^{[5
,6
,7
]}

Bernard, Matthew J. ^{[1
]}

Diaz, Johnny A. ^{[3
]}

Heering, Kylie Y. ^{[3
]}

Huang, Rong Rong ^{[8
]}

Low, Jin-Yih ^{[9
]}

Matulionis, Nedas ^{[10
]}

Navone, Nora M. ^{[11
]}

Ye, Huihui

Zoubeidi, Amina ^{[12
,13
]}

Christofk, Heather R. ^{[5
,10
,14
]}

Rettig, Matthew B. ^{[6
]}

Reiter, Robert E. ^{[6
]}

Haffner, Michael C. ^{[15
,16
,17
]}

Boutros, Paul C. ^{[5
,6
,7
,18
]}

Shirihai, Orian S. ^{[2
,4
,19
]}

Divakaruni, Ajit S. ^{[2
]}

Goldstein, Andrew S. ^{[3
,5
,6
,14
,20
]}

机构：

[1] Univ Calif Los Angeles, Mol Biol Interdept Program, Los Angeles, CA 90095 USA

[2] Univ Calif Los Angeles, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA

[3] Univ Calif Los Angeles, Dept Mol Cell & Dev Biol, Los Angeles, CA 90095 USA

[4] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Endocrinol, Los Angeles, CA 90095 USA

[5] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA

[6] Univ Calif Los Angeles, David Geffen Sch Med, Dept Urol, Los Angeles, CA 90095 USA

[7] Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA 90095 USA

[8] Univ Calif Los Angeles, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA

[9] Fred Hutchinson Canc Res Ctr, Div Human Biol, Seattle, WA 98109 USA

[10] Univ Calif Los Angeles, David Geffen Sch Med, Dept Biol Chem, Los Angeles, CA 90095 USA

[11] Univ Texas MD Anderson Canc Ctr, Dept GU Med Oncol, Houston, TX 77030 USA

[12] Univ British Columbia, Dept Urol Sci, Vancouver, BC, Canada

[13] Vancouver Prostate Ctr, Vancouver, BC, Canada

[14] Univ Calif Los Angeles, Eli & Edythe Broad Stem Cell Res Ctr, Los Angeles, CA 90095 USA

[15] Fred Hutchinson Canc Res Ctr, Div Human Biol, Seattle, WA 98109 USA

[16] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA

[17] Univ Washington, Dept Lab Med & Pathol, Seattle, WA 98195 USA

[18] Univ Calif Los Angeles, Inst Precis Hlth, Los Angeles, CA 90095 USA

[19] Ben Gurion Univ Negev, Sch Med, Dept Clin Biochem, Beer Sheva, Israel

[20] Univ Calif Los Angeles, Mol Biol Inst, Los Angeles, CA 90095 USA

来源：

CELL REPORTS | 2023年 / 42卷 / 10期

基金：

美国国家卫生研究院;

关键词：

OXIDATIVE-PHOSPHORYLATION; TRANSCRIPTIONAL PROGRAM; MASS-SPECTROMETRY; METFORMIN; ENZALUTAMIDE; ANTIANDROGEN; MITOCHONDRIA; DEGRADATION; PROGRESSION; EXPRESSION;

D O I：

10.1016/j.celrep.2023.113221

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页数：28

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