Weber 2016 Abstract Mito Xmas Meeting Innsbruck
|Loss of PTEN in prostate cancer cells leads to a switch to succinate-mediated mitochondrial respiration associated with increased expression of NaDC3 and HIF-1alpha.|
Metabolic changes are a hallmark of prostate cancer cells. In order to reveal novel targets that could be used for therapeutic intervention, we performed a comprehensive metabolic analysis of different human and murine prostate cancer cell lines.
In line with previous studies we found that loss of phosphatase and tensin homolog (PTEN), a major driver of prostate cancer cells, is associated with high glycolytic activity, increased lactate production and elevated expression of hexokinase 2 (HK2). This increased glycolytic activity corresponds with weak activity of pyruvate dehydrogenase (PDH), which drives pyruvate into oxidative phosphorylation, and high expression of the PDH inhibitor PDK1 (pyruvate dehydrogenase kinase). Mitochondrial ROUTINE respiration was elevated in all PTEN- compared to PTEN+ cells. While digging deeper into these pathways we showed that high lactate production in PTEN- cells leads to a switch in mitochondrial respiration towards complex II. We found that PTEN- PCa cells favour succinate as substrate for oxidative phosphorylation while lowering the capacity to use glutamate and pyruvate. In addition, we found that the Na(+)-dependent dicarboxylate transporter NaDC 3, responsible for succinate uptake into cells, is elevated in PTEN- compared to PTEN+ cells and that HIF-1alpha, stabilized by succinate, is increased in cells lacking PTEN.
Our data show that uptake of succinate via the NaDC 3 transporter could be an efficient way to overcome hypoxia and to fulfill the energy requirements in PTEN- PCa cells and that intervening with this pathway may offer a new way for treatment of PCa.
Labels: MiParea: Respiration, Genetic knockout;overexpression, Patients Pathology: Cancer
Organism: Human, Mouse Tissue;cell: Genital Preparation: Intact cells, Permeabilized cells Enzyme: Complex I, Complex II;succinate dehydrogenase, TCA cycle and matrix dehydrogenases Regulation: Substrate Coupling state: ROUTINE Pathway: N, NS HRR: Oxygraph-2k Event: Poster Labelled by author
- Weber A(1), Pencik J(2), Kenner L(2), Klocker H(1), Eder IE(1)
- Dept Urology, Medical Univ Innsbruck, Austria
- Clinical Inst Pathol, Medical Univ Vienna, Austria