Squalene Epoxidase Metabolic Dependency Is a Targetable Vulnerability in Castration-Resistant Prostate Cancer
Xun Shangguan1, Zehua Ma2, Minghao Yu1
1Department of Urology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Abstract:
Considering the dismal prognosis of castration-resistant prostate cancer (CRPC), it is critical to identify novel therapeutic targets in this disease. Malignant cells have metabolic dependencies distinct from their healthy counterparts, resulting in therapeutic vulnerabilities. Although PTEN and TP53 are the most frequently comutated or codeleted driver genes in lethal CRPC, the metabolic dependencies underlying PTEN/p53 deficiency-driven CRPC for therapeutic intervention remain largely elusive. In this study, PTEN/p53 deficient tumors were determined to be reliant on cholesterol metabolism. Moreover, PTEN/p53 deficiency transcriptionally upregulated squalene epoxidase (SQLE) via activation of sterol regulatory element-binding protein 2 (SREBP2). In addition, PTEN deficiency enhanced the protein stability of SQLE by inhibiting the PI3K/Akt/GSK3β-mediated proteasomal pathway. Consequently, SQLE increased cholesterol biosynthesis to facilitate tumor cell growth and survival. Pharmacologic blockade of SQLE with FR194738 profoundly suppressed the invasive program of CRPC. Collectively, these results demonstrate a synergistic relationship between SQLE and PTEN/p53 deficiency in CRPC development and progression. Therefore, pharmacologic interventions targeting SQLE may hold promise for the treatment of patients with CRPC.
Significance:
This study reveals PTEN and p53 deficiency confers a dependence on SQLE-mediated cholesterol metabolism, providing insights for new therapeutic strategies for treating castration-resistant prostate cancer.
Insights
Castration-resistant prostate cancer (CRPC) with PTEN/p53 deficiency relies on cholesterol metabolism. Targeting squalene epoxidase (SQLE) offers a promising therapeutic strategy for CRPC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Metabolic Pathways
Background:
- Castration-resistant prostate cancer (CRPC) has a poor prognosis, necessitating novel therapeutic targets.
- PTEN and TP53 mutations are common in lethal CRPC, but their metabolic dependencies are not well understood.
- Understanding metabolic vulnerabilities in CRPC is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the metabolic dependencies of PTEN/p53 deficient CRPC.
- To identify novel therapeutic targets for CRPC based on metabolic vulnerabilities.
- To explore the role of cholesterol metabolism in PTEN/p53 deficient CRPC.
Main Methods:
- Analysis of PTEN/p53 deficient tumors to identify metabolic dependencies.
- Investigating the transcriptional regulation of squalene epoxidase (SQLE) by PTEN/p53 deficiency via SREBP2.
- Examining the effect of PTEN deficiency on SQLE protein stability through the PI3K/Akt/GSK3β pathway.
- Pharmacologic blockade of SQLE using FR194738 in CRPC models.
Main Results:
- PTEN/p53 deficient tumors exhibit a reliance on cholesterol metabolism.
- PTEN/p53 deficiency upregulates SQLE expression through SREBP2 activation.
- PTEN deficiency stabilizes SQLE protein via the PI3K/Akt/GSK3β pathway, enhancing cholesterol biosynthesis.
- Inhibition of SQLE with FR194738 suppressed CRPC invasion and progression.
Conclusions:
- PTEN/p53 deficiency creates a dependence on SQLE-mediated cholesterol metabolism in CRPC.
- Targeting SQLE represents a potential therapeutic strategy for CRPC.
- The synergistic relationship between SQLE and PTEN/p53 deficiency highlights SQLE as a key driver in CRPC progression.
