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Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients
Published on: November 19, 2019
Targeting the Metabolic Enzyme PGAM2 Overcomes Enzalutamide Resistance in Castration-Resistant Prostate Cancer by
Zhen Li1,2,3, Kang Ning1,2, Diwei Zhao1,2
1Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, China.
Abstract:
The next-generation androgen receptor (AR) inhibitor enzalutamide is the mainstay treatment for metastatic prostate cancer. Unfortunately, resistance occurs rapidly in most patients, and once resistance occurs, treatment options are limited. Therefore, there is an urgent need to identify effective targets to overcome enzalutamide resistance. Here, using a genome-wide CRISPR-Cas9 library screen, we found that targeting a glycolytic enzyme, phosphoglycerate mutase PGAM2, significantly enhanced the sensitivity of enzalutamide-resistant prostate cancer cells to enzalutamide both in vivo and in vitro. Inhibition of PGAM2 together with enzalutamide treatment triggered apoptosis by decreasing levels of the antiapoptotic protein BCL-xL and increasing activity of the proapoptotic protein BAD. Mechanistically, PGAM2 bound to 14-3-3ζ and promoted its interaction with phosphorylated BAD, resulting in activation of BCL-xL and subsequent resistance to enzalutamide-induced apoptosis. In addition, high PGAM2 expression, which is transcriptionally regulated by AR, was associated with shorter survival and rapid development of enzalutamide resistance in patients with prostate cancer. Together, these findings provide evidence of a nonmetabolic function of PGAM2 in promoting enzalutamide resistance and identify PGAM2 inhibition as a promising therapeutic strategy for enzalutamide-resistant prostate cancer.
Significance:
PGAM2 promotes resistance to enzalutamide by activating antiapoptotic BCL-xL and suppressing apoptosis, indicating that PGAM2 is a potential target for overcoming enzalutamide resistance in prostate cancer.
Insights
Targeting phosphoglycerate mutase (PGAM2) overcomes enzalutamide resistance in prostate cancer. Inhibiting PGAM2 restores sensitivity to enzalutamide by promoting apoptosis, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Enzalutamide is a key treatment for metastatic prostate cancer.
- Resistance to enzalutamide is a major clinical challenge, limiting treatment options.
- New therapeutic targets are needed to overcome enzalutamide resistance.
Purpose of the Study:
- To identify novel targets for overcoming enzalutamide resistance in prostate cancer.
- To investigate the role of phosphoglycerate mutase PGAM2 in enzalutamide resistance.
Main Methods:
- Genome-wide CRISPR-Cas9 library screening was employed.
- In vitro and in vivo studies were conducted using prostate cancer cells.
- Molecular mechanisms involving PGAM2, BAD, BCL-xL, and 14-3-3ζ were investigated.
Main Results:
- PGAM2 inhibition sensitized enzalutamide-resistant prostate cancer cells to enzalutamide.
- PGAM2 inhibition induced apoptosis by modulating BCL-xL and BAD.
- PGAM2 interacts with 14-3-3ζ to promote BAD phosphorylation, leading to BCL-xL activation and resistance.
- High PGAM2 expression correlates with shorter survival and rapid resistance in patients.
Conclusions:
- PGAM2 plays a nonmetabolic role in promoting enzalutamide resistance.
- PGAM2 inhibition is a potential therapeutic strategy for enzalutamide-resistant prostate cancer.
