Elevated Expression of Glycerol-3-Phosphate Phosphatase as a Biomarker of Poor Prognosis and Aggressive Prostate Cancer

SIMPLE SUMMARY: A number of diseases, including cancers, can be diagnosed with “biomarkers”, such as specific proteins, hormones, or mutations in some genes. These molecules reflect abnormal processes in the affected organs, and are useful for diagnosis and disease treatment options. The need exists to have reliable markers for various types of cancers such as prostate cancer (PC). Many cancers show high utilization of glucose for their growth; we recently identified an enzyme, glycerol 3-phosphate phosphatase (G3PP), that can modulate glucose utilization by cells. Our work revealed a high expression of G3PP in prostate cancer cells in patients with aggressive tumors. With further validation, G3PP expression in prostate cancer tumors may become a useful prognostic biomarker and aid in the management of patients with PC. ABSTRACT: The limitations of the biomarker prostate-specific antigen (PSA) necessitate the pursuit of biomarkers capable of better identifying high-risk prostate cancer (PC) patients in order to improve their therapeutic management and outcomes. Aggressive prostate tumors characteristically exhibit high rates of glycolysis and lipogenesis. Glycerol 3-phosphate phosphatase (G3PP), also known as phosphoglycolate phosphatase (PGP), is a recently identified mammalian enzyme, shown to play a role in the regulation of glucose metabolism, lipogenesis, lipolysis, and cellular nutrient-excess detoxification. We hypothesized that G3PP may relieve metabolic stress in cancer cells and assessed the association of its expression with PC patient prognosis. Using immunohistochemical staining, we assessed the epithelial expression of G3PP in two different radical prostatectomy (RP) cohorts with a total of 1797 patients, for whom information on biochemical recurrence (BCR), metastasis, and mortality was available. The association between biomarker expression, biochemical recurrence (BCR), bone metastasis, and prostate cancer-specific survival was established using log-rank and multivariable Cox regression analyses. High expression of G3PP in PC epithelial cells is associated with an increased risk of BCR, bone metastasis, and PC-specific mortality. Multivariate analysis revealed high G3PP expression in tumors as an independent predictor of BCR and bone metastasis development. High G3PP expression in tumors from patients eligible for prostatectomies is a new and independent prognostic biomarker of poor prognosis and aggressive PC for recurrence, bone metastasis, and mortality.