SLC4A4 is a novel driver of enzalutamide resistance in prostate cancer

Hao-Jie Chen; Ming-Ming Yu; Jia-Cheng Huang; Fu-Ying Lan; Hai-Hong Liao; Zi-Han Xu; Yong-Jiang Yu; Yi-Chen Huang; Fang Chen

doi:10.1016/j.canlet.2024.217070

SLC4A4 is a novel driver of enzalutamide resistance in prostate cancer

Cancer Lett. 2024 Aug 10:597:217070. doi: 10.1016/j.canlet.2024.217070. Epub 2024 Jun 14.

Authors

Hao-Jie Chen¹, Ming-Ming Yu², Jia-Cheng Huang³, Fu-Ying Lan³, Hai-Hong Liao⁴, Zi-Han Xu³, Yong-Jiang Yu⁵, Yi-Chen Huang⁶, Fang Chen⁷

Affiliations

¹ Department of Urology, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200062, China; Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China.
² Department of Ultrasound in Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
³ Department of Urology, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200062, China.
⁴ Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China.
⁵ Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China. Electronic address: yuyongjiang@xinhuamed.com.cn.
⁶ Department of Urology, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200062, China. Electronic address: drhuangyichen@163.com.
⁷ Department of Urology, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200062, China. Electronic address: chenfang01@sjtu.edu.cn.

PMID: 38880227
DOI: 10.1016/j.canlet.2024.217070

Abstract

The androgen receptor signaling inhibitor (ARSI) enzalutamide (Enz) has shown critical efficacy in the treatment of advanced prostate cancer (PCa). However, the development of drug resistance is a significant factor contributing to mortality in PCa patients. We aimed to explore the key mechanisms of Enz-resistance. Through analysis of GEO databases, we identified SLC4A4 as a novel driver in Enz resistance. Long-term Enz treatment leads to the up-regulation of SLC4A4, which in turn mediates P53 lactylation via the NF-κB/STAT3/SLC4A4 axis, ultimately leading to the development of Enz resistance and progression of PCa. SLC4A4 knockdown overcomes Enz resistance both in vitro and in vivo. Hence, our results suggest that targeting SLC4A4 could be a promising therapeutic strategy for Enz resistance. STATEMENT OF SIGNIFICANCE: SLC4A4 is a novel driver of enzalutamide resistance.

Keywords: Enzalutamide; PCa; Prostate cancer; Resistance; SLC4A4.

MeSH terms

Animals
Benzamides*
Cell Line, Tumor
Drug Resistance, Neoplasm* / genetics
Gene Expression Regulation, Neoplastic / drug effects
Humans
Male
Mice
NF-kappa B / genetics
NF-kappa B / metabolism
Nitriles*
Phenylthiohydantoin* / analogs & derivatives
Phenylthiohydantoin* / pharmacology
Phenylthiohydantoin* / therapeutic use
Prostatic Neoplasms* / drug therapy
Prostatic Neoplasms* / genetics
Prostatic Neoplasms* / pathology
STAT3 Transcription Factor / genetics
STAT3 Transcription Factor / metabolism
Signal Transduction / drug effects
Sodium-Bicarbonate Symporters* / genetics
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism
Up-Regulation
Xenograft Model Antitumor Assays

Substances

Benzamides
enzalutamide
NF-kappa B
Nitriles
Phenylthiohydantoin
STAT3 protein, human
STAT3 Transcription Factor
TP53 protein, human
Tumor Suppressor Protein p53
SLC4A4 protein, human
Sodium-Bicarbonate Symporters