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. While PTEN and TP53 are the most frequently co-mutated or co-deleted 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. Pharmacological 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, pharmacological interventions targeting SQLE may hold promise for the treatment of CRPC patients.

The androgen receptor (AR) signaling is a key contributor to tumorigenesis and the progression of prostate cancer. A subset of patients may develop neuroendocrine (NE) features, resulting in resistance to androgen deprivation therapy and poor prognosis. In this study, we combined immunostaining and bulk and single-cell transcriptome analyses to better characterize the status of AR in prostate cancer with neuroendocrine differentiation. The exploration of online datasets indicated the existence of ARHIGH/NEHIGH prostate cancer and revealed that these double-high cases are majorly present in castration-resistant prostate cancer with a less neuroendocrine-transdifferentiated state. We then reviewed 8,194 prostate cancer cases with available immunohistochemistry reports and found 2.3% cases (n = 189) that showed at least one of the NE markers (chromogranin A, synaptophysin, and neural cell adhesion molecule 1) being positive in at least 5% of epithelial cells. Within these 189 cases, we observed that 81.0% cases (n = 153) showed AR positive and 19.0% (n = 36) showed AR negative. Patients with AR loss tumors demonstrated a correlation with adverse clinical stages, indicating a trade-off between AR and advanced disease in neuroendocrine differentiation. Using multiplex immunofluorescence staining, we observed the co-localization of AR and NE markers in prostate cancer cells. In addition, data mining of single-cell transcriptome further confirmed the existence of ARHIGH/NEHIGH prostate cancer cells in castration-resistant samples and suggested that AR still exerts its androgen response and anti-apoptotic effect in these double-high cells. Thus, our study provides a better understanding of AR signaling in the cellular plasticity of prostate cancer with neuroendocrine differentiation and allows new insights into the therapeutic development.

Background: This study aimed to evaluate the effectiveness of 18 F-fluoro-2-deoxy-D-glucose Positron emission tomography/computed tomography ( 18 F-FDG PET/CT) in predicting prognosis and characterizing the intratumoral glucose uptake of neuroendocrine prostate cancer (NEPC). Methods: We retrospectively reviewed 189 NEPC patients from two medical centers between January 2009 and April 2021. Of these, 44 patients met the inclusion criteria. The maximum standardized uptake value (SUVmax) was measured to assess the metabolic state of NEPC and comparison were made between different histopathological subtypes. Kaplan-Meier and Cox regression analyses were performed to evaluate the predictive value of SUVmax on overall survival (OS) and progression-free survival (PFS).Results: This study analyzed 44 NEPC patients and found that 13 patients had small cell neuroendocrine carcinoma (SCNC), while 31 were diagnosed with adenocarcinoma with neuroendocrine differentiation (Ad-NED) based on histopathology, and a positive correlation was found between SUVmax and SCNC via Spearman correlation test (r s = 0.60, p < 0.0001). Furthermore, SUVmax demonstrated good diagnostic accuracy in differentiating SCNC from Ad-NED (area under the curve 0.88, 95% confidence interval [CI] 0.76-0.99). Kaplan-Meier survival analyses and univariate analyses revealed that patients with SUVmax > 10.2 had a significantly shorter OS than patients with SUVmax ≤ 10.2 (hazard ratio = 4.83, 95% CI 1.45-16.1, p = 0.01). Conclusions:The histopathological subtypes in NEPC showed a close correlation with the glucose metabolic activity of primary tumors as assessed by 18 F-FDG PET/