GSTM2 is a key molecular determinant of resistance to SG-ARIs

Chaohao Li; Jinpeng Liu; Daheng He; Fengyi Mao; Xiongjian Rao; Yue Zhao; Nadia A. Lanman; Majid Kazemian; Elia Farah; Jinghui Liu; Chrispus M. Ngule; Zhuangzhuang Zhang; Yanquan Zhang; Yifan Kong; Lang Li; Chi Wang; Xiaoqi Liu

doi:10.1038/s41388-022-02444-1

GSTM2 is a key molecular determinant of resistance to SG-ARIs

Chaohao Li
, Jinpeng Liu
, Daheng He
, Fengyi Mao
, Xiongjian Rao
, Yue Zhao
, Nadia A. Lanman
, Majid Kazemian
, Elia Farah
, Jinghui Liu
, Chrispus M. Ngule
, Zhuangzhuang Zhang
, Yanquan Zhang
, Yifan Kong
, Lang Li
, Chi Wang
, Xiaoqi Liu

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

8 Scopus citations

Abstract

Prostate cancer (PCa) continues to threaten men’s health, and treatment targeting the androgen receptor (AR) pathway is the major therapy for PCa patients. Several second-generation androgen receptor inhibitors (SG-ARIs), including enzalutamide (ENZ), apalutamide (APA) and darolutamide (DARO), have been developed to better block the activity of AR. Unavoidably, emergence of resistance to these novel drugs still persists. Herein, we identified glutathione S-transferase Mu 2 (GSTM2) as an important determinant in the acquisition of resistance to SG-ARIs. Elevated GSTM2 was detected in enzalutamide-resistant (ENZ-R) PCa, and overexpression of GSTM2 in naïve enzalutamide-sensitive (ENZ-S) cells effectively transformed them to ENZ-R PCa. Aryl hydrocarbon receptor (AhR), the upstream transcription factor, was implicated in the overexpression of GSTM2 in ENZ-R cells. Mechanistically, GSTM2 antagonized the effect of ENZ by rescuing cells from oxidative stress-associated damage and activation of p38 MAPK pathway. Surprisingly, high GSTM2 levels also associated with cross-resistance to APA and DARO. Taking together, these results provide new insight to ameliorate resistance to SG-ARIs and improve treatment outcome.

Original language	English
Pages (from-to)	4498-4511
Number of pages	14
Journal	Oncogene
Volume	41
Issue number	40
DOIs	https://doi.org/10.1038/s41388-022-02444-1
State	Published - Sep 30 2022

Bibliographical note

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.

Funding

The research is generously supported by NIH R01 CA157429 (XL), R01 CA196634 (XL), R01 CA264652 (XL), R01 CA256893 (XL). This research is also supported by the Biospecimen Procurement & Translational Pathology, Biostatistics and Bioinformatics, Redox Metabolism, and Flow Cytometry and Immune Monitoring Shared Resources of the University of Kentucky Markey Cancer Center (P30CA177558). We thanks Dr. Alumkal Joshi for the generous sharing of the RNA-seq raw data, and Eleanor Erikson for the critical reading and editing of the manuscript.

Funders	Funder number
National Institutes of Health (NIH)	R01 CA264652, R01 CA256893, R01 CA196634, R01 CA157429
National Institutes of Health (NIH)
University of Kentucky Markey Cancer Center	P30CA177558
University of Kentucky Markey Cancer Center

ASJC Scopus subject areas

Molecular Biology
Genetics
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41388-022-02444-1

Cite this

@article{9a2e9d291cf249288936ef53f03f31a4,

title = "GSTM2 is a key molecular determinant of resistance to SG-ARIs",

abstract = "Prostate cancer (PCa) continues to threaten men{\textquoteright}s health, and treatment targeting the androgen receptor (AR) pathway is the major therapy for PCa patients. Several second-generation androgen receptor inhibitors (SG-ARIs), including enzalutamide (ENZ), apalutamide (APA) and darolutamide (DARO), have been developed to better block the activity of AR. Unavoidably, emergence of resistance to these novel drugs still persists. Herein, we identified glutathione S-transferase Mu 2 (GSTM2) as an important determinant in the acquisition of resistance to SG-ARIs. Elevated GSTM2 was detected in enzalutamide-resistant (ENZ-R) PCa, and overexpression of GSTM2 in na{\"i}ve enzalutamide-sensitive (ENZ-S) cells effectively transformed them to ENZ-R PCa. Aryl hydrocarbon receptor (AhR), the upstream transcription factor, was implicated in the overexpression of GSTM2 in ENZ-R cells. Mechanistically, GSTM2 antagonized the effect of ENZ by rescuing cells from oxidative stress-associated damage and activation of p38 MAPK pathway. Surprisingly, high GSTM2 levels also associated with cross-resistance to APA and DARO. Taking together, these results provide new insight to ameliorate resistance to SG-ARIs and improve treatment outcome.",

author = "Chaohao Li and Jinpeng Liu and Daheng He and Fengyi Mao and Xiongjian Rao and Yue Zhao and Lanman, \{Nadia A.\} and Majid Kazemian and Elia Farah and Jinghui Liu and Ngule, \{Chrispus M.\} and Zhuangzhuang Zhang and Yanquan Zhang and Yifan Kong and Lang Li and Chi Wang and Xiaoqi Liu",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2022",

month = sep,

day = "30",

doi = "10.1038/s41388-022-02444-1",

language = "English",

volume = "41",

pages = "4498--4511",

number = "40",

}

TY - JOUR

T1 - GSTM2 is a key molecular determinant of resistance to SG-ARIs

AU - Li, Chaohao

AU - Liu, Jinpeng

AU - He, Daheng

AU - Mao, Fengyi

AU - Rao, Xiongjian

AU - Zhao, Yue

AU - Lanman, Nadia A.

AU - Kazemian, Majid

AU - Farah, Elia

AU - Liu, Jinghui

AU - Ngule, Chrispus M.

AU - Zhang, Zhuangzhuang

AU - Zhang, Yanquan

AU - Kong, Yifan

AU - Li, Lang

AU - Wang, Chi

AU - Liu, Xiaoqi

PY - 2022/9/30

Y1 - 2022/9/30

N2 - Prostate cancer (PCa) continues to threaten men’s health, and treatment targeting the androgen receptor (AR) pathway is the major therapy for PCa patients. Several second-generation androgen receptor inhibitors (SG-ARIs), including enzalutamide (ENZ), apalutamide (APA) and darolutamide (DARO), have been developed to better block the activity of AR. Unavoidably, emergence of resistance to these novel drugs still persists. Herein, we identified glutathione S-transferase Mu 2 (GSTM2) as an important determinant in the acquisition of resistance to SG-ARIs. Elevated GSTM2 was detected in enzalutamide-resistant (ENZ-R) PCa, and overexpression of GSTM2 in naïve enzalutamide-sensitive (ENZ-S) cells effectively transformed them to ENZ-R PCa. Aryl hydrocarbon receptor (AhR), the upstream transcription factor, was implicated in the overexpression of GSTM2 in ENZ-R cells. Mechanistically, GSTM2 antagonized the effect of ENZ by rescuing cells from oxidative stress-associated damage and activation of p38 MAPK pathway. Surprisingly, high GSTM2 levels also associated with cross-resistance to APA and DARO. Taking together, these results provide new insight to ameliorate resistance to SG-ARIs and improve treatment outcome.

AB - Prostate cancer (PCa) continues to threaten men’s health, and treatment targeting the androgen receptor (AR) pathway is the major therapy for PCa patients. Several second-generation androgen receptor inhibitors (SG-ARIs), including enzalutamide (ENZ), apalutamide (APA) and darolutamide (DARO), have been developed to better block the activity of AR. Unavoidably, emergence of resistance to these novel drugs still persists. Herein, we identified glutathione S-transferase Mu 2 (GSTM2) as an important determinant in the acquisition of resistance to SG-ARIs. Elevated GSTM2 was detected in enzalutamide-resistant (ENZ-R) PCa, and overexpression of GSTM2 in naïve enzalutamide-sensitive (ENZ-S) cells effectively transformed them to ENZ-R PCa. Aryl hydrocarbon receptor (AhR), the upstream transcription factor, was implicated in the overexpression of GSTM2 in ENZ-R cells. Mechanistically, GSTM2 antagonized the effect of ENZ by rescuing cells from oxidative stress-associated damage and activation of p38 MAPK pathway. Surprisingly, high GSTM2 levels also associated with cross-resistance to APA and DARO. Taking together, these results provide new insight to ameliorate resistance to SG-ARIs and improve treatment outcome.

UR - https://www.scopus.com/pages/publications/85137037941

UR - https://www.scopus.com/pages/publications/85137037941#tab=citedBy

U2 - 10.1038/s41388-022-02444-1

DO - 10.1038/s41388-022-02444-1

M3 - Article

C2 - 36038661

AN - SCOPUS:85137037941

SN - 0950-9232

VL - 41

SP - 4498

EP - 4511

JO - Oncogene

JF - Oncogene

IS - 40

ER -

GSTM2 is a key molecular determinant of resistance to SG-ARIs

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this