Differential Expression of Glucose Transporters and Hexokinases in Prostate Cancer with a Neuroendocrine Gene Signature: A Mechanistic Perspective for ¹⁸F-FDG Imaging of PSMA-Suppressed Tumors

Abstract

Although the incidence of de novo neuroendocrine prostate cancer (PC) is rare, recent data suggest that low expression of prostate-specific membrane antigen (PSMA) is associated with a spectrum of neuroendocrine hallmarks and androgen receptor (AR) suppression in PC. Previous clinical reports indicate that PCs with a phenotype similar to neuroendocrine tumors can be more amenable to imaging by ¹⁸F-FDG than by PSMA-targeting radioligands. In this study, we evaluated the association between neuroendocrine gene signature and ¹⁸F-FDG uptake-associated genes including glucose transporters (GLUTs) and hexokinases, with the goal of providing a genomic signature to explain the reported ¹⁸F-FDG avidity of PSMA-suppressed tumors. <b>Methods:</b> Data-mining approaches, cell lines, and patient-derived xenograft models were used to study the levels of 14 members of the <i>SLC2A</i> family (encoding GLUT proteins), 4 members of the hexokinase family (genes <i>HK1</i>-<i>HK3</i> and <i>GCK</i>), and PSMA (<i>FOLH1</i> gene) after AR inhibition and in correlation with neuroendocrine hallmarks. Also, we characterize a neuroendocrine-like PC (NELPC) subset among a cohort of primary and metastatic PC samples with no neuroendocrine histopathology. We measured glucose uptake in a neuroendocrine-induced in vitro model and a zebrafish model by nonradioactive imaging of glucose uptake using a fluorescent glucose bioprobe, GB2-Cy3. <b>Results:</b> This work demonstrated that a neuroendocrine gene signature associates with differential expression of genes encoding GLUT and hexokinase proteins. In NELPC, elevated expression of <i>GCK</i> (encoding glucokinase protein) and decreased expression of <i>SLC2A12</i> correlated with earlier biochemical recurrence. In tumors treated with AR inhibitors, high expression of <i>GCK</i> and low expression of <i>SLC2A12</i> correlated with neuroendocrine histopathology and PSMA gene suppression. GLUT12 suppression and upregulation of glucokinase were observed in neuroendocrine-induced PC cell lines and patient-derived xenograft models. A higher glucose uptake was confirmed in low-PSMA tumors using a GB2-Cy3 probe in a zebrafish model. <b>Conclusion:</b> A neuroendocrine gene signature in neuroendocrine PC and NELPC associates with a distinct transcriptional profile of GLUTs and hexokinases. PSMA suppression correlates with GLUT12 suppression and glucokinase upregulation. Alteration of ¹⁸F-FDG uptake-associated genes correlated positively with higher glucose uptake in AR- and PSMA-suppressed tumors. Zebrafish xenograft tumor models are an accurate and efficient preclinical method for monitoring nonradioactive glucose uptake.