Endocrine Abstracts

Metabolic reprogramming resulting in significant alterations of the energy metabolism is a hallmark of prostate cancer (PCa). In this study we performed a comprehensive metabolic analysis of various human (LNCaP, DuCaP, PC-3, Du145) and murine PCa cell lines differing in the expression of the tumor suppressor phosphatase and tensin homolog (PTEN). In line with previous studies we found that PTEN^- PCa cells (LNCaP, PC-3) had a higher glycolytic activity than PTEN⁺ PCa cells (DuCaP, Du145) with increased lactate production and elevated expression of hexokinase 2 (HK2) mRNA. PTEN⁻ PCa cells also exhibited lower activity of pyruvate dehydrogenase (PDH) and higher expression of the PDH inhibitor PDK1 (pyruvate dehydrogenase kinase), thereby attenuating pyruvate flux into Krebs cycle and pyruvate-fuelled oxidative phosphorylation (OXPHOS). Overall, mitochondrial routine respiration was higher in PTEN⁻ compared to PTEN⁺ cells, with a significant switch towards succinate-(complex II) fuelled respiration at the expense of pyruvate (complex I) mediated respiration. Notably, sodium – dependent dicarboxylate cotransporter (NaDC3/SLC13A3), a transporter protein that mediates succinate uptake, was elevated in PTEN^- PCa cells as shown by Western blotting. In line with an increased succinate level, which is known to stabilize the hypoxia-inducible factor HIF1α immunofluorescent staining confirmed increased expression of HIF1α in PTEN⁻ compared to PTEN⁺ cell lines. In conclusion, our data suggest that the uptake of succinate via NaDC 3 enhances a hypoxia-response and oxidative phosphorylation in order to fulfil increased energy requirements of PCa cells. An intervening with this pathway may offer a new way for the treatment of PCa.

Presenting author: Anja Weber, Department of Urology, Anichstraße 35, 6020 Innsbruck, Austria. Email: [email protected].